FOXO factors and breast cancer: outfoxing endocrine resistance

in Endocrine-Related Cancer

The majority of metastatic breast cancers cannot be cured and present a major public health problem worldwide. Approximately 70% of breast cancers express the estrogen receptor, and endocrine-based therapies have significantly improved patient outcomes. However, the development of endocrine resistance is extremely common. Understanding the molecular pathways that regulate the hormone sensitivity of breast cancer cells is important to improving the efficacy of endocrine therapy. It is becoming clearer that the PI3K–AKT–forkhead box O (FOXO) signaling axis is a key player in the hormone-independent growth of many breast cancers. Constitutive PI3K–AKT pathway activation, a driver of breast cancer growth, causes down-regulation of FOXO tumor suppressor functions. This review will summarize what is currently known about the role of FOXOs in endocrine-resistance mechanisms. It will also suggest potential therapeutic strategies for the restoration of normal FOXO transcriptional activity.

Abstract

The majority of metastatic breast cancers cannot be cured and present a major public health problem worldwide. Approximately 70% of breast cancers express the estrogen receptor, and endocrine-based therapies have significantly improved patient outcomes. However, the development of endocrine resistance is extremely common. Understanding the molecular pathways that regulate the hormone sensitivity of breast cancer cells is important to improving the efficacy of endocrine therapy. It is becoming clearer that the PI3K–AKT–forkhead box O (FOXO) signaling axis is a key player in the hormone-independent growth of many breast cancers. Constitutive PI3K–AKT pathway activation, a driver of breast cancer growth, causes down-regulation of FOXO tumor suppressor functions. This review will summarize what is currently known about the role of FOXOs in endocrine-resistance mechanisms. It will also suggest potential therapeutic strategies for the restoration of normal FOXO transcriptional activity.

Introduction

Breast cancer is a leading cause of female death worldwide. Each year, almost 1.4 million women are diagnosed with breast cancer, and the disease will be responsible for 450 000 deaths (Siegel et al. 2011). This review will highlight the importance of forkhead box O (FOXO) activity in the development of endocrine resistant breast cancer. FOXO transcription factors are key regulators of gene expression in numerous physiological and pathological processes. FOXO nuclear exclusion is a key feature of breast cancer cells transformed by oncogenic PI3K–AKT signaling (Zhang et al. 2011, Fig. 1). It is also becoming clear that aberrant FOXO activity promotes a number of characteristic features of hormone-independent breast cancer growth, including altered estrogen receptor (ER) function. Although breast cancer cells express multiple FOXOs, most studies have focused on the FOXO3A isoform. FOXOs are subject to extensive post-translational regulation, and targeting these processes may provide therapeutic strategies to overcome resistance.

Figure 1

Download Figure

Figure 1

Genetic changes found in different forms of breast cancer that cause chronic activation of the PI3K–AKT pathway. Afflicted components of the pathway are highlighted, and the specific nature of the most common mutations described: (1) HER2 receptor amplification; (2) PI3CA (p110) activating mutations; (3) deletion of INPP4B gene; (4) PTEN inactivating mutations/deletions; and (5) AKT1/AKT3 activating mutations.

Citation: Endocrine-Related Cancer 23, 2; 10.1530/ERC-15-0461

FOXO gene family

The FOXO genes encode for the O-subfamily of proteins that belong to the larger family of forkhead transcription factors. Forkhead transcription factors are named after the Drosophila melanogaster forkhead gene (fkh; Weigel et al. 1989), and to date, ∼200 members have been identified; in species that range in complexity from Saccharomyces cerevisiae that has four members (Wijchers et al. 2006) to human with 43 members (Katoh & Katoh 2004). These proteins are characterized solely by the presence of a highly conserved DNA-binding domain (DBD) called the FOX, forkhead (FKD) (Weigel & Jackle 1990), or alternatively the winged-helix domain (Gajiwala & Burley 2000). On the basis of minor sequence variation within the FOX-domain, FOX family members are divided into sub-families, that are each designated with a different letter (currently there are 17 subfamilies, ranging from A to Q). Outside of the FOX-domain, there is little shared homology, and the structure and function of FOX proteins is found to be incredibly diverse. As is the case for members of all large transcription factor families, FOX genes been implicated in the transcriptional regulation of an extensive range of biological processes. In the case of FOX genes, such reported functions include regulation of cell proliferation, differentiation, DNA-repair, apoptosis, metabolism, and also immune-regulation (Lam et al. 2006,Wijchers et al. 2006, Ziegler 2006, Laoukili et al. 2007).

In mammalian species, there are four members of the FOXO gene family. Three of the members exhibit a high degree of sequence homology: FOXO1 (previously called FKHR), FOXO3A (FKHRL1), and FOXO4 (AFX). The fourth member of the family, the FOXO6 gene, exhibits major structural differences compared with the other three family members.

In keeping with a high degree of sequence homology between DBDs shared by members of the same forkhead subfamily, all FOXO proteins share the same DNA-binding specificity, recognizing gene regulatory elements that share a central core DNA motif consisting of the nucleotides TTGTTTAC. Profiling of genome-wide FOXO DNA-binding has been mostly been performed in the study of the immune-system, with FOXO cistrome having been determined for B-cells and macrophages. (Fan et al. 2010, Lin et al. 2010, Litvak et al. 2012). These studies are somewhat limited in their ability to determine direct downstream effects of FOXO activity. However, Eijkelenboom et al. (2013) used an inducible cell-culture system (DLD1 colon carcinoma cells) to measure the direct effects of FOXO3A activation. Analysis of the FOXO3A cistrome reveals that the factor functions predominantly as a classical transcriptional activator. Furthermore, a significant part of FOXO3A gene-regulation is found to proceed through enhancer regulatory elements.

FOXOs are expressed throughout the human body, and there is broad overlap in their expression patterns. However, each factor is uniquely enriched within particular tissue types: FOXO1 in adipose and liver tissue, FOXO3A in the brain, and FOXO4 in skeletal muscle. Uniquely, the FOXO6 gene appears to be expressed almost exclusively in adult brain (Furuyama et al. 2000). Despite tissue specific enrichment, there clearly exists some level of functional redundancy between FOXO factors, with the net activity of multiple co-expressed FOXOs having an accumulative effect on gene expression. This is highlighted by observations drawn from compound gene-knockout experiments. Initially, such studies that utilized single- or double-knockouts to disrupt one or two FOXO factors did not yield the expected tumor-prone phenotype (see the section covering ‘Tumor suppressor function of FOXOs’). However, broad somatic-cell deletion of all three FOXO factors yields the full tumor phenotypes characterized by thymic lymphomas and hemangiomas (Castrillon et al. 2003, Hosaka et al. 2004, Paik et al. 2007). Strikingly, despite widespread expression of FOXOs throughout the body, carcinogenesis is restricted to thymocytes and endothelial-derived cell lineages in this model. At present it is not clear why this is the case. Interestingly, hemangiomas are a characteristic feature of Cowden's disease, which is caused by germline inactivation of the phosphatase and tensin homolog (PTEN) gene, leading to hyperactivity of the PI3K–AKT pathway. The mechanism by which constitutive PI3K–AKT pathway activation causes down-regulation of FOXO activity is discussed in more detail below.

Tumor suppressor function of FOXOs

Interestingly, FOXO1, 3, and 4 were implicated in cancer biology immediately upon their discovery. FOXO1 was discovered as a fusion protein (the fusion partner being either the PAX3 or PAX7 DBD), the product of a chromosomal translocation event within the cells of pediatric alveolar rhabdomyosarcoma (Galili et al. 1993, Sublett et al. 1995, Schmitt-Ney & Camussi 2015). FOXO3A and FOXO4 were discovered as fusion partners with the mixed-lineage leukemia gene in acute myeloid leukemias (Parry et al. 1994). However, experiments that attempted to recapitulate a tumor phenotype by overexpressing these fusion proteins were largely unsuccessful (Lagutina et al. 2002), suggesting instead that loss of FOXO function might be the crucial step in mediating carcinogenesis. It is now clear that FOXOs are tumor-suppressors, and suppression of their activity contributes to a number of malignant processes. For instance, FOXOs are well characterized as transcriptional regulators of a large number of genes implicated in carcinogenesis. These include: i) cell-cycle regulatory components such as p27kip1 (CDKN1B; Dijkers et al. 2000); ii) pro-apoptotic proteins like TRAIL (TNFSF10; Modur et al. 2002); iii) DNA repair enzymes such as GADD45 (Kobayashi et al. 2005); iv) detoxification pathway enzymes such as manganese superoxide dismutase 2 (Adachi et al. 2007); and v) genes involved in autophagy and the maintenance of cellular organelle and protein homeostasis (Webb & Brunet 2014).

Breast cancer and hormone dependence

There are four recognized major molecular subtypes of breast cancer, which are classed according to gene expression profiling (Perou et al. 2000). The vast majority of breast cancers (∼70%) are ER positive (ER+). They belong to either the Luminal-A group (mostly ER+ and histologically low grade); or the luminal-B group (mostly ER+ and often higher grade). Endocrine therapy is the most efficacious treatment for these forms of breast cancer. The human epidermal growth factor receptor 2 (HER2, expressed by the ERRB gene)-amplified group, have been a great clinical success due to the development of effective HER2-targeting therapies (Bergamaschi et al. 2006, Chin et al. 2006). In contrast, the triple-negative breast cancer group (also known as basal-like breast cancers), so-called because they lack expression of ER, progesterone receptor (PR), and HER2, are a patient group who currently only have chemotherapy options (Perou 2011).

Endocrine therapy

The growth and development of normal breast tissue is governed by the signaling action of the ovarian hormones, 17β-estradiol (E2, the predominant estrogen) and progesterone, which signal through the nuclear receptors ER and PR respectively. Two major isoforms of ER exist, ERα and ERβ, which are encoded by separate genes, ESR1 and ESR2 (ER1 and ER2) respectively (reviewed by Jia et al. (2015)). The PR also exists as two isoforms, PR-A and PR-B, the products of transcription from two alternative promoters of the PR (PGR) gene (reviewed by Jacobsen & Horwitz (2012)). Immunohistochemical analysis of normal breast tissue, obtained from pre-menopausal women, shows that ERα, PR-A, and PR-B are expressed within the inner luminal epithelial layer of the acini and intralobular ducts, and also the myoepithelial layer of the interlobular ducts (Li et al. 2010). ERβ exhibits a more widespread expression pattern, being found within the epithelial, myoepithelial, and stromal cells of both acini and ducts. Normal growth of female breast tissue occurs during puberty, during the menstrual cycle and also during pregnancy; with E2 regulating the process of ductal elongation and branching (Deroo et al. 2009), and progesterone regulating side-branching, and lobular development (Conneely et al. 2007). The expression levels of ER and PR isoforms are also dynamically regulated during these processes (Arendt & Kuperwasser 2015). The classic function of ligand activated ERα is transcriptional regulation of hundreds of genes involved in processes such as proliferation, differentiation, survival, invasion, many of which are particularly relevant for cancer biology.

Seventy percent of all breast cancers exhibit detectable expression of the ERα and/or the PR (the role of PR is reviewed in depth by Brisken (2013) and Seton-Rogers (2015)). A plethora of studies have demonstrated that ERα-signaling functions as a major driver of breast cancer tumorigenesis; promoting cancer-cell proliferation, survival, and invasive behavior (Osborne & Schiff 2011). In contrast ERβ is expressed in 50% of breast cancers (Borgquist et al. 2008), and it appears to possess ERα-independent function in breast cancer; but it remains much less well characterized, and studies have yielded conflicting results regarding its clinical significance (reviewed by Burns & Korach (2012)). In this review, ER will refer to the ERα isoform, unless otherwise stated.

Clinically, when compared with the behavior of ER-negative (−) cancers, affected patients are more likely to present with indolent disease, bone metastases, and late disease reoccurrence (Blanco et al. 1990). However, in contrast with triple-negative breast cancers, endocrine therapies that target and inhibit ER function, mean that ER+ breast cancer patients have more effective treatment options available to them.

Currently, three broad classes of endocrine therapy are commonly used to treat ER+ breast cancers: i) selective ER modifiers, e.g., tamoxifen, which binds directly to the ER and inhibits its transcriptional activity; ii) selective ER down-regulators, e.g., fulvestrant, which bind to the ER and induce its degradation; and iii) aromatase inhibitors (AIs), e.g., letrozole, anastrozole (both non-steroidal/reversible) and excemestane (steroidal/irreversible), which act to inhibit aromatase enzymes expressed throughout peripheral tissues and the tumor itself, thus reducing the production, and therefore circulating levels of estrogen. Endocrine therapy has been successful, and the outcome for millions of breast cancer patients has been significantly improved over the past 30 years (Bliss et al. 2012).

Endocrine resistance

Although long-term remission is possible, a significant proportion of patients will develop some form of resistance to endocrine therapy. Four commonly occurring clinical scenarios are as follows: i) the breast cancer initially responds positively to endocrine therapy, but eventually acquires resistance. Often, in such cases, additional positive responses can be temporally gained from the use of alternative endocrine therapies; however, the cancer eventually evolves resistance to all therapy; ii) disease progression following an initial response to endocrine therapy, followed by a renewed response to the same therapy when administered years later; iii) de novo resistance to all endocrine therapies, or the acquisition of this resistance soon after the patient begins adjuvant treatment; and iv) de novo resistance to some, but not all therapies. There is pre-clinical data to suggest that de novo and acquired forms of resistance share common pathways (see section discussing ‘Preclinical studies’). However, some clinical scenarios also support the existence of drug (or class of drug)-specific forms of resistance.

FOXOs in breast cancer

FOXO3A appears to be a key isoform in mediating hormone-independent breast cancer growth. FOXO3A overexpression significantly inhibits the growth of breast tumors in vitro and in animal models (Hu et al. 2004, Yang et al. 2008, Zou et al. 2008), and also negatively impacts upon angiogenesis; a process required for malignant tumor growth, invasion, and metastasis (Potente et al. 2005). Hu et al. (2004) observed that cytoplasmic FOXO3A staining correlated with the expression of inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ), raised phospho-AKT and overall poorer patient survival. Gargini et al. (2015) showed that FOXO proteins, in concert with Bim (a member of the BCL2 protein family), mediate the PI3K–AKT driven cancer stem-cell phenotype within three commonly used breast cancer cell-lines (MDA-MB-231, MCF7-Ras, and MCF10A) (Gargini et al. 2015). Furthermore, Lv et al. (2013) found that C-terminus of Hsc70-interacting protein induced apoptosis resistance to chemotherapeutics in normal and breast cancer cells, specifically by modulation of the PI3K–AKT–FOXO3A–Bim signaling axis (Lv et al. 2013).

Interaction between FOXOs and ER signaling

The function of FOXO3A as a tumor repressor appears to be dependent on the co-expression of ER. Sisci et al. (2013) observed that overexpression of FOXO3A induces a decrease in the malignant behavior (motility, invasiveness, and anchorage-independent growth) of an in vitro ER+ cancer cell model, while eliciting the opposite effect in ER− (or ER-silenced) cell-lines. Immunohistochemical analysis performed in the same study revealed that on the one hand, nuclear FOXO3A staining inversely correlated with invasive phenotype of ER+ breast tumors, but on the other hand positively correlated with invasion of ER− tumors.

This ER-dependent tumor repressor activity of FOXOs can be explained, at least partly, by their role as the mediators of crosstalk between ER and growth factor receptor signaling. Several reports have recently suggested a functional interaction between ER and FOXO family members. Estrogen-activated ER binds to FOXO1, FOXO3A, and FOXO4; which depending on the cellular context, exhibit co-activator or co-repressor functions on estrogen-responsive DNA regulatory elements (Schuur et al. 2001, Zhao et al. 2001, Zou et al. 2008). Interestingly, ER has also shown to interact with a diverse number of FOX proteins including FOXE1 (Park et al. 2012), FOXP1 (Halacli & Dogan 2015), and FOXA1 (Wright et al. 2014); suggestive of a conserved mechanism of association between the receptor and the wider forkhead family. The significance of the ER–FOX interaction is highlighted by the role of FOXA1 as a pioneer factor, which facilitates ER DNA-binding at cis-regulatory elements within heterochromatin. Indeed, FOXA1 expression is positively correlated with a good prognosis of ER+ breast cancers, probably because FOXA1 expression is indicative of a functional ER (reviewed in depth by Tokunaga et al. (2014)).

Currently, no data exists to whether the potential pioneer activity FOXOs (reviewed by Lalmansingh et al. (2012)) can also modulate ER DNA-binding in breast cancer. However, Morelli et al. (2010) demonstrated that FOXO3A, functioning as a classical co-repressor of ER, could exert a protective role in ER+ breast tumors. In agreement with this observation, targeted inhibition of AKT isoform 2 activity in these cells inhibited ER-directed transcription via FOXO3A activation.

Other molecular mechanisms of endocrine resistance

HER2 amplification is a well-established marker for endocrine resistance (Arpino et al. 2004). A meta-analysis showed that HER2+ metastatic breast cancers are less responsive to all forms of endocrine therapy (De Laurentiis et al. 2005). The molecular mechanisms of HER2 mediated hormone resistance are becoming clearer. HER2-containing heterodimers, particularly HER2–HER3 heterodimers, induce PI3K–AKT pathway activation (Tzahar et al. 1996), and HER2 amplification is positively correlated with AKT activity in breast carcinomas (Stal et al. 2003, Zhou et al. 2004, Tokunaga et al. 2006). However, <10% of ER+ breast cancers are also HER2+. Thus, the underlying resistance mechanism(s) for the majority of ER+ breast cancers remains to be elucidated.

Pre-clinical studies have implicated growth factor signaling pathways in the estrogen-independent activation of ER. In addition to HER2, tyrosine receptor kinases implicated in the development of endocrine resistance include: epidermal growth factor receptor (EGFR), insulin-like growth factor receptor 1 (IGF1R), insulin receptor, receptor originated from nantes, and fibroblast growth factor receptor 1 (Frogne et al. 2009, McClaine et al. 2010, Turner et al. 2010, Fox et al. 2011). All of these receptors converge on the PI3K–AKT signaling pathway, hyper-activation of which promotes the acquired estrogen-independent growth of ER+ breast cancer cells (Miller et al. 2010). They also activate the rat sarcoma viral oncogene homolog (RAS)/ERK signaling pathway, contributing to estrogen-independent ER activation; even in cultured breast cancer cells that are grown in the presence of tamoxifen. Under these conditions, ERK phosphorylates ER at serine 118 (Ser118), a site that is normally phosphorylated in response to estrogen-stimulation; itself an ERK-independent mechanism (Kato et al. 1995, Bunone et al. 1996).

In addition to perturbed growth factor signaling, another mechanism of endocrine resistance involves the inhibition of transcriptional co-activators, such as steroid receptor co-activator 1, that interacts with ER (Shang & Brown 2002). Decreased interactions between ER and the nuclear receptor co-repressor can also lead to tamoxifen resistance (Lavinsky et al. 1998). Indeed, Shang et al. (2000) showed that tamoxifen recruits co-repressors to ER-responsive gene promoters, but not co-activators.

Autophagy, the process by which a cell degrades and recycles damaged or unrequired organelles, has also recently been revealed to play a central role in endocrine resistance. The unfolded protein response (UPR) is an evolutionary conserved stress-responsive pathway, activated when unfolded or misfolded proteins accumulate within the cells endoplasmic reticulum. The master regulator of ubiquitin specific peptidase (USP) signaling is the protein chaperone glucose-regulated protein 78 (GRP78), which integrates signals from several pathways to concurrently inhibit stress-induced apoptosis and stimulate a prosurvival autophagic response (Cook et al. 2012, Clarke & Cook 2015). Elevated GRP78 expression has been observed within all breast cancer molecular subtypes, as compared with the levels of expression in normal breast tissue (Cook et al. 2012). Within breast cancer cells GRP78 controls the autophagic response via signaling through the 5′-AMP-activated protein kinase and mammalian target of rapamycin (mTOR) signaling pathways (Cook et al. 2012). Cook et al. (2014) observed that treatments such as tamoxifen and fulvestrant can stimulate the pro-survival UPR and autophagy signaling in breast cancer cells.

De-regulation of PI3K–AKT signaling in breast cancer

Constitutive activation of PI3K–AKT signaling is recognized as a major driver of cancer progression. Dysregulation of the pathway has been implicated in an extensive range of human malignancies; including breast, ovarian, head and neck, and colorectal cancer. It is also a central player in the mechanisms leading to endocrine resistance of breast cancer (Tokunaga et al. 2014). Several causal mechanisms have been reported; all consequent to DNA mutations in genes encoding principal components of the pathway (see Fig. 1). The exact nature and frequency of mutation is unique to each type of cancer (Thorpe et al. 2015).

The PI3K–AKT pathway is extremely well characterized and has been reviewed in considerable detail by others (Fruman & Rommel 2014, Martini et al. 2014, Thorpe et al. 2015). Briefly, the PI3K protein/lipid kinases are grouped into classes I (which itself is further divided into IA and IB), II, or III according to their structure and specific substrate specificity. The best characterized of these are class IA PI3Ks, which are heterodimeric; each composed of a catalytic subunit (p110) and a regulatory adaptor protein (p85). They function to transduce input signals from a wide variety of upstream sources, such as growth factor/hormone stimulated-receptor tyrosine kinases (RTKs), G-protein coupled receptors, and also oncogenic signaling molecules such as RAS.

The p110 catalytic subunit has three isoforms: p110α, p110β, and p110δ that are encoded for by three individual genes; PIK3CA, PIK3CB, and PIK3CD respectively. The p85 regulatory subunit also has three isoforms: p85α, p55α, and p110δ which are also transcribed from three different genes; PIK3R1, PIK3R2, and PIK3R3 respectively.

Following growth factor/hormone activation of a RTK, the p85 subunit binds via its SH2-domain to the phosphorylated-protein motifs of the RTK. This recruitment has the effect of lifting p85-mediated inhibition of the p110 subunit, allowing p85 to catalyze conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) into phosphatidylinositol 3,4,5-trisphosphate (PIP3). The tumor suppressor gene PTEN encodes a phosphatase that removes phosphate from PIP3; and thus functions as a negative regulator of the PI3K–AKT pathway. Another phosphatase with tumor-suppressor function is inositol polyphosphate-4-phosphatase, type II (INPP4B), the gene product of which also negatively regulates the pathway, by depleting cellular levels of PIP2. Upon generation, PIP3 functions as a secondary messenger, attaching to the pleckstrin-homology-domain of proteins such as v-akt murine thymoma viral oncogene homolog 1 (AKT) and pyruvate dehydrogenase kinase isoform 1. PIP3 binding to AKT targets this Ser/threonine (Thr) kinase to the cell-membrane where it can be activated by phosphorylation at Ser473 by mTOR, and then at Thr308 by phosphoinositide dependent kinase 1. AKT activation initiates cascades of downstream phosphorylation events that impact on several aspects of cellular behavior that are of relevance to cancer; including cell cycle progression, enhanced chemotherapeutic resistance, elevated cell metabolism, increased resistance to hypoxia, and tumor metastasis.

According to The Cancer Genome Atlas PIK3CA is frequently mutated gene in breast cancer, present at a frequency of 49 and 32% in ER+ luminal A and B subtypes; 42% of HER2-enriched, and 7% of basal-like breast cancer subtypes. Other mutations impacting upon PI3K–AKT pathway activity, such as PTEN mutation/loss and INPP4B loss were also commonly found in all four subtypes (Cancer Genome Atlas N 2012). Recent studies have reported that alterations to the AKT3 gene (e.g. the MAGI–AKT3 gene fusion), leading to constitutive AKT activation, also occur in some ER+ and triple-negative breast cancers (Kirkegaard et al. 2010, Banerji et al. 2012, O'Hurley et al. 2014).

The PI3K–AKT pathway can also be activated via signaling crosstalk with the ER. The ER binds to the p85 regulatory subunit of PI3K, in an estrogen-dependent manner, resulting in downstream activation of AKT (Simoncini et al. 2000). The treatment of breast cancer cells with E2 stimulates cellular proliferation via PI3K–AKT pathway activation (Lee et al. 2005). Interestingly, this activity was found to be ERα-dependent, while ERβ appears not to play a role.

The role of PI3K–AKT–FOXO signaling in breast cancer

Mechanisms of FOXO regulation

Cancer associated FOXO dysregulation activity can arise from genetic mutations (chromosomal translocation; described above) or through disruption of their transcriptional activity. In-keeping with the pleiotropic functioning of FOXOs, their activity is subjected to a variety of different regulatory mechanisms depending upon the cellular context. These can be broadly divided into those which are exerted at the transcriptional level, and those which involve post-translational modifications.

Transcriptional regulation of FOXOs

Recent studies have suggested that the expression of FOXO1 and FOXO3A is subjected to modulation at the gene-promoter level by the transcription factor E2F1. Nowak et al. (2007) found that E2F1, in a glioblastoma in-vitro model, induced the transcription of both of FOXO1 and FOXO3A. Both gene promoters contained evolutionary conserved E2F1 binding-sites, and therefore, they are highly likely to be direct targets of E2F1. Interestingly, the ER regulated E2F1 expression has been associated with tamoxifen resistance in ER+ breast cancer cells (Montenegro et al. 2014).

FOXO gene transcription is regulated by nutrient intake and insulin signaling in an in vivo insulin resistance model. Reduced nutrient availability in an artificially induced insulin-resistance state, stimulated transcription of FOXO1, FOXO3A, and FOXO4 in rat hepatocytes (Imae et al. 2003). Recently, observations of an in vivo model of fasted blood glucose revealed the cAMP–protein kinase A (PKA) stimulated transcriptional co-activator p300 induces transcription of FOXO1 (Wondisford et al. 2014).

Post-translational regulation of FOXO activity

Post-translational protein modification of FOXOs has been extensively studied, and it is apparent the function of these factors is subjected to multiple layers of regulation. Although, apparently complex, FOXO post-translational regulation appears to operate by modulating two complementary mechanisms: i) altered FOXO subcellular localization and ii) modulation of FOXO DNA-binding and/or association with other DNA-binding proteins. The net action of these processes can profoundly impact upon FOXO-regulated gene transcription. Outlined below are the most extensively characterized FOXO protein modifications:

Phosphorylation

Brunet et al. (1999) discovered that FOXOs were subject to regulation by the PI3K–AKT signaling pathway. They demonstrated that AKT possesses high binding affinity for the FOXO3A protein motif RXRXXS/T, and upon binding to the FOXO factor, catalyzes the phosphorylation of three specific amino-acids: Thr32, Ser253, and Ser315. All FOXO proteins, with the exception of FOXO6, contain evolutionary conserved variants of these phosphorylation sites (see Fig. 2). The phosphorylated-FOXO3A isoform is subsequently translocated out of the nucleus and sequestered in the cytoplasm. Each of the three phosphorylation events contributes to this translocation by a different mechanism. Phosphorylated Thr32 is directly involved in regulating the binding of 14-3-3 chaperone proteins (Brunet et al. 2002). The residue Ser253 resides within a nuclear localization sequence (NLS), and the addition of a negatively charged phospho-group to this basic sequence physically disrupts the signal, and inhibits the re-entry of cytoplasmic FOXOs into the nucleus. In contrast, Ser315 phosphorylation results in the unmasking of a nuclear export sequence (NES), which mediates physical association with the exportin chromosome region maintenance 1 (CRM1; also known as exportin-1 or Xpo1 protein). Thus, cultured cells treated with the CRM1 inhibitor leptomycin exhibit predominant FOXO nuclear localization and this inhibition of nuclear export is independent of FOXO phosphorylation status (Brunet et al. 2002). The importance of the NES is also highlighted by the behavior of FOXO6, which is the only FOXO to lacks the NES, and unlike the other three subfamily members; it is predominantly a nuclear protein (Jacobs et al. 2003).

Figure 2

Download Figure

Figure 2

Location of post-translational modifications that regulate FOXO transcriptional activity. A schematic representation of the four members of the human FOXO family are shown with amino-acid positions of important structural features and modifications highlighted.

Citation: Endocrine-Related Cancer 23, 2; 10.1530/ERC-15-0461

Other inhibitory kinases

The conserved RXRXXS/T protein motif also serves as a binding-substrate for several other kinases such as PKA, PKC, and serum and glucocorticoid-induced kinase (SGK; Pearce et al. 2010). Thus, several growth factors signaling converge on the FOXOs to negatively regulate their function. Interestingly, in vitro experiments utilizing dominant-negative mutant forms of AKT or SGK, inhibiting their respective pathways, both lead to nuclear accumulation of FOXOs; suggesting a non-redundant role for at least some kinases in targeting FOXOs to the cytoplasm (Brunet et al. 2001). It remains unclear why such redundancy exists, but it may be the case that the activity of each kinase is specific to a particular physiological/cellular context.

ERK phosphorylates FOXO3A on the amino-acid residues: Ser294, Ser344, and Ser425, and similarly to AKT-mediated phosphorylation, these promote the cytoplasmic sequestration of the factor. However, an additional consequence of these modifications is they target the FOXO3A for proteasomal degradation. It has been proposed that this may occur due to increased interaction with the E3-ligase, MDM2 (Yang et al. 2008; see ‘Ubiquitination’ section).

The IκB kinase (IKK), a component of the NFκB pathway, phosphorylating Ser644, appears to inhibit FOXO3A activity in a similar manner (Hu et al. 2004). This may be of particular relevance to breast tumorigenesis, as constitutive activation of the kinase has been linked to the disease. Furthermore, Chen et al. (2015a) have recently shown that activated-IKKβ is required to sustain the ‘stemness’ of breast cancer stem cells.

Casein kinase 1 (CK1) plays a role in cell differentiation and its de-regulation has been shown to contribute to cancer development. CK1 phosphorylates the amino acid residues Ser318 and Ser321 of the FOXO protein, but only following the prior phosphorylation of Ser315 by SGK. In vitro experiments have shown that these phosphorylation events occur in a specific hierarchical fashion: phosphorylation by SGK creates the consensus recognition sequence motif for CK1 phosphorylation (S/T(P)XXS/T) at Ser318, which in turn creates a second consensus sequence for the CK1 catalysed phosphorylation of Ser321. These modifications are generally believed to influence the rate of nuclear export of FOXOs, potentially through differential interaction with components of the nuclear export complex, though this remains to be proven (Rena et al. 2002).

Dual specificity tyrosine phosphorylated and regulated kinase 1A

Dual specificity tyrosine phosphorylated and regulated kinase 1A (DYRK1A), a Ser/Thr kinase, catalyses the phosphorylation of Ser325, in a manner that appears to be independent of SGK-and-CK1 kinase activity, and this acts to induce the nuclear accumulation of FOXOs. DYRK1A mediated modifications also appears to occur independently of PI3K–AKT activity. However, phosphorylation of Ser325 does seem to exhibit a synergistic effect when occurring in concert with SGK-and-CK1-mediated phosphorylation. This also may occur as the result of further enhancement of the association of FOXOs with the nuclear export complex; though this also needs to experimentally verified (Gao et al. 2012).

Co-factor interactions

The phosphorylation-directed binding of 14-3-3 proteins can also negatively impact the ability of FOXOs to interact with other transcriptional regulatory proteins. FOXOs participate in several known transcriptional complexes, such as: i) ER (Schuur et al. 2001, Zhao et al. 2001); ii) p53 (Wang et al. 2008); and iii) CREB binding protein (CBP)/p300. In the case of CBP/p300, the phospho-Thr32/Ser253-isoform has been shown to have lost the ability to physically associate with these transcriptional co-activator proteins (Wang et al. 2009, 2012a), and thus, this modification negates the transcriptionally favorable chromatin remodeling that this protein association generally promotes. CBP/p300 also functions to acetylate the lysine residues within the FOX-domain, thus repressing FOXO DNA-binding activity (see ‘FOXO acetylation’ section).

Activation by kinases

There are some reported phosphorylation events that have a positive impact on FOXO activity. For instance, protein kinases such as MST1 (Lehtinen et al. 2006), JNK (Essers et al. 2004), and CDK1 (Yuan et al. 2008), promote nuclear accumulation of FOXOs, generally in response to signals arising from cellular stress (e.g. oxidative stress).

FOXO acetylation

The acetylation of FOXOs changes their transcriptional activity. The acetylation-status of a given FOXO is the product of an equilibrium between the action of histone deacetylases (HDACs), such as silent information regulator 1 (SIRT1) and SIRT2; and histone acetyl transferases (HATs), such as CBP/p300 (Daitoku et al. 2011).

Acetylation by HATs deactivates FOXOs through two sequential steps. First, when FOXO are acetylated at three conserved lysine residues (corresponding to Lys242, Lys245, and Lys262 of FOXO1; see Fig. 2), their DNA binding capacity is dramatically reduced (van der Heide & Smidt 2005, Matsuzaki et al. 2005). Secondly, the acetylated isoform of FOXO has increased potential as an AKT substrate, and it is thus ‘sensitized’ to PI3K–AKT induced translocation out of the nucleus.

The deacetylation of FOXOs is performed by both class I HDACs and the class III, NAD-dependent histone HDACs (members of the Sirtuin protein family). The effect of SIRT1 activity on the transcription regulatory function of FOXOs varies for different subsets of FOXO-regulated genes. It appears that some FOXO-regulated genes, especially genes related to cell-cycle control and senescence, are up-regulated; while pro-apoptotic genes are down-regulated. For instance, SIRT1-mediated acetylation increases the ability of FOXOs to induce cell-cycle arrest and promote resistance to oxidative stress (e.g. up-regulation of p27KIP1 and GADD45; Daitoku et al. 2004, Kobayashi et al. 2005). In contrast, SIRT1 negatively regulates the FOXO-induced expression of pro-apoptotic genes. Wang et al. (2015), investigating the role of SIRT1 in an in vitro oxidative stress-induced apoptosis model, observed that a decrease in FOXO3A-acetylation accompanied a corresponding increase in ubiquitination (see ‘Ubiquitination’ section). The subsequent degradation of the protein leads to down-regulation of FOXO3A-regulated pro-apoptotic genes. Also, in an in vitro mouse myoblast oxidative stress model, the expression of FOXO1, FOXO3A, and FOXO4 were all found to be indispensable for anti-apoptotic effects of SIRT1 activity (Hori et al. 2013). The underlying mechanisms responsible for this selective effect of SIRT1 on FOXO3A-regulated genes are not understood.

Other members of SIRT family like SIRT2 and SIRT3 can also interact and deacetylate FOXOs (Jacobs et al. 2008, Sundaresan et al. 2009, Wang et al. 2012b). Also, class I HDAC4/5 has been observed to recruit the deacetylase activity of HDAC3 to FOXO, which results in activation of FOXO-regulated genes (Mihaylova et al. 2011).

Ubiquitination

Expression levels of FOXOs are also governed by ubiquitin-regulated proteolysis. The PI3K–AKT, NFκB, and ERK signaling pathways have all been implicated in regulating this process. The E3-ubiquitin ligase S-phase kinase-associated protein 2 (SKP2) is recruited by the AKT-phosphorylated Ser256 of cytoplasmic FOXO1 and proteasomal-mediated degradation of FOXO1 can be rapidly induced in response to PI3K–AKT pathway stimulation (Huang et al. 2005). In contrast, the NFκB appears to be the relevant signaling pathway for targeting FOXO3A to the proteasome. Hu et al. (2004) found that the IKKβ mediated phosphorylation of FOXO3A at Ser664, targeted the protein for ubiquitin-dependent proteolysis; however, as or yet, the ubiquitin responsible remains to be identified.

Another E3-protein ligase MDM2 is activated by ERK-pathway activity, to induce both mono- and poly-ubiquitination of FOXOs. Interestingly, these two modifications of FOXO have very different effects on their function. The monoubiquitinated isoform of FOXO cannot be acetylated, thus the modification maintains the factor in an in-active, but ‘transcriptionally poised’ state (van der Horst et al. 2006, Brenkman et al. 2008). It is thought that this form of the protein can be rapidly activated, in response to certain stress stimuli (e.g. oxidative stress), most likely through the action of the deubiquitinating enzyme USP7/herpesvirus-associated ubiquitin-specific protease (van der Horst et al. 2006). In contrast, polyubiquitination targets FOXO proteins for proteasome-mediated degradation, and so, long-term inhibition of FOXO transcriptional activity (Fu et al. 2009). Activation of the PI3K–AKT pathway has been implicated in stimulating FOXO proteolysis in several different cellular contexts (Matsuzaki et al. 2003, Plas & Thompson 2003, Aoki et al. 2004). In addition to AKT, other kinases such as IKK and ERK have been observed to promote the proteolysis of FOXO3A (Hu et al. 2004, Yang et al. 2008).

It has been proposed, that in response to certain cellular conditions (e.g. high expression levels of MDM2), monoubiquitination of FOXO4 can promote its subsequent polyubiquitination by SKP2.

Therapeutics targeting the PI3K–AKT–FOXO signaling axis

Clinical interventions that are able to restore FOXO tumor suppressor function, could potentially be used as therapeutic strategies to overcome endocrine resistance (Hill et al. 2014a). To this end, potential drug targets that warrant future investigation include: i) growth factor signaling pathways that converge on, and negatively regulate FOXO; ii) the cellular transportation machinery responsible for the nuclear/cytoplasmic shuttling of FOXOs; iii) proteasomes that target FOXOs for degradation; and iv) the DNA-binding activity of the FOXO proteins themselves (see Fig. 3).

Figure 3

Download Figure

Figure 3

Potential therapeutic targets that could be used to restore FOXO signaling activity in breast cancer cells: (1) kinase signaling pathways that promote nuclear export and sequestration of FOXOs in the cytoplasm; (2) chaperone proteins such as 14-3-3 and exportins; (3) proteasomal degradation of FOXOs; and (4) FOXO interaction with DNA-promoter targets and transcriptional machinery.

Citation: Endocrine-Related Cancer 23, 2; 10.1530/ERC-15-0461

PI3K–AKT pathway inhibition

Preclinical studies

As has been described, numerous studies have implicated PI3K–AKT–FOXO dysregulation as possessing a significant contributory role in the development of endocrine resistance. This has spurred the trial of endocrine/PI3K-inhibition combination therapies, and initial pre-clinical studies have generally yielded encouraging results in terms of the potential utility of these strategies to prevent or overcome resistance. Unfortunately, the examination of FOXO activity was beyond the scope of the majority of these studies; though it is likely that future experiments will demonstrate that FOXOs have a contributory role in many of the positive effects observed.

The simultaneous treatment of ER+/HER2+ breast cancer cells (the BT-474 cell-line) with the anti-HER2 antibody trastuzumab (Herceptin) and tamoxifen, synergistically inhibits their growth in vitro, and also within a xenograft mouse model (Argiris et al. 2004, Wang et al. 2005). Targeting HER2 was found to potently inhibit both the PI3K–AKT and ERK signaling pathway in these experiments. Another pre-clinical study found that treating tamoxifen-resistant breast cancer cells (MCF7 cells expressing constitutively active AKT) with the mTOR inhibitors CCI-779 (temsirolimus) or rapamycin, restored the sensitivity of these cells to tamoxifen-induced growth inhibition (deGraffenried et al. 2004). The mTOR1 complex is a downstream target of PI3K–AKT signaling; directing cellular metabolism and growth, and its dysregulation is frequently implicated in human malignancy (Dibble & Cantley 2015).

Miller et al. (2010) observed that their in vitro acquired resistance model is heavily reliant on PI3K–AKT–mTOR signaling. They created several long-term estrogen deprivation (LTED) breast cancer cell-lines to study the mechanisms of escape from E2 dependent growth. Molecular characterization of the LTEDs revealed significantly increased AKT and mTOR activity compared with the corresponding parental cell-lines. Furthermore, the PI3K/mTOR dual inhibitor, BEZ235, was extremely effective at inducing growth arrest and apoptosis of LTEDs, and also effectively prevented the emergence of new resistant cancer cell populations (Miller et al. 2010). In a subsequent study, Miller et al. (2011) observed an E2-independent ER transcriptional activity; that directs the cell-cycle progression of both LTEDs and primary cultures of AI treated breast tumors. Combined down-regulation of ER (fulvestrant) and PI3K inhibition with BKM120 (Buparlisib) induces a regression of tumors comprising these cells (Miller et al. 2011).

To date, only a small number of studies have directly examined FOXO activity in response to PI3K inhibition within breast cancer cells. Recently, Hill et al. (2014a,b) reported that the compound ETP-45658, a pyrazolopyrimidine derivative that is a PI3K inhibitor, potently inhibited the growth of breast cancer cells via cell-cycle arrest (observed in MCF7 and MDA-MB231 breast cancer cell-line models). The authors observed treatment of MCF7 cells inhibited and increased phosphorylation (Ser253) and nuclear accumulation of FOXO3A, respectively, and specifically induced a FOXO-dependent transcriptional response enriched for cell-cycle related genes (Hill et al. 2014b). Chu et al. (2015) found that treatment of human breast cancer cells with a 2-aryl benzimidazole compound, that likely targets EGFR and HER2 signaling activity, inhibited the phosphorylation of FOXO1 (Ser319 and Ser256) and FOXO3A (Thr32 and Thr24), promoting the translocation of these FOXO proteins from the cytoplasm into the nucleus.

Although there is little data in the context of breast cancer, restoration of FOXO activity by PI3K–AKT inhibition has also been observed in the treatment of a variety of other human cancers. For instance, treatment of chronic myeloid leukaemia with the pan tyrosine kinase inhibitor imatinib (Gleevec), inhibited PI3K–AKT signaling, and effectively restored FOXO3A transcriptional activity (Fernandez de Mattos et al. 2004, Essafi et al. 2005). A similar effect is also observed in osteosarcoma cells treated with the PI3K–AKT inhibitor Grifolin (Jin et al. 2007).

Clinical trials

Clinical trials have also shown the efficacy of PI3K–AKT pathway inhibition as a strategy to overcome endocrine resistance. Two trials have investigated the utility of treating ER+/HER2+ metastatic breast cancers with combination of anastrozole (AI) treatment and HER2 inhibition; with either trastuzumab or latatinib. In both trials, progression-free survival (PFS) was found to be superior in the combination arms (Johnston et al. 2009, Kaufman et al. 2009).

More recently, some large clinical trials have explored whether targeting mTORC1 is of benefit to patients with ER+ breast tumors; that have relapsed following previous AI treatment. In the tamoxifen plus RAD001 phase-II trial, metastatic breast cancer patients were randomized to tamoxifen combined with the mTOR inhibitor everolimus (formerly known as RAD001) or tamoxifen alone (Bachelot et al. 2012). Statistically significant improvements in PFS and clinical benefit were seen in the combination arm (8.6 months vs 4.6 months with tamoxifen alone, hazard ratio (HR) 0.54). Of note, subgroup analysis revealed that the benefit received from combination therapy is only seen in patients with acquired resistance.

In the breast cancer trials of oral everolimus 2 (BOLERO-2) phase-III trial, post-menopausal with ER+ HER2− advanced breast cancer were randomized to groups receiving everolimus or placebo, combined with the AI exemestane (Baselga et al. 2012, Yardley et al. 2013). The final study results (median follow-up of 18 months) showed that everolimus combined with the AI improves PFS in patients with ER+ HER− cancers that had been previously treated with non-steroidal AIs (letrozole or anastrozole). The primary end-point PFS was more than doubled in the combination treatment arm (7.8 months vs 3.2 months in the combination and exemestane alone arms, respectively; HR 0.89; 95% CI 0.38–0.54; P<0.0001; Yardley et al. 2013). Furthermore, subgroup analysis showed that clear improvement in PFS in elderly patients (improved median PFS by 2.82 months in patients >65 years of age, HR 0.59; and by 5.26 months in patients ≥70 years of age, HR 0.45; in the combination and exemestane alone arms respectively), an outcome of particular clinical importance considering the typical age distribution of women with ER+ advanced breast cancer (Pritchard et al. 2013).

However, despite being generally well-tolerated, there are still some significant toxicity issues caused by everolimus treatment. Commonly reported symptoms include fatigue, stomatitis, rashes, hyperglycemia, hypolipidemia, myelosuppression, and diarrhea. Also, 3% of patients have reported non-infectious pneumonia which appears to be immunologically mediated. These are typical class-effects associated with mTOR inhibitors. Fortunately most of these adverse effects are not life-threatening and can be managed by proper prevention and management strategies (reviewed by Rugo (2015)).

These data are generally encouraging that strategies that employ simultaneous targeting of PI3K–AKT and ER pathways may be of benefit to breast cancer patients with acquired resistance. Indeed, on the basis of the BOLERO-2 study, FDA approval was granted for the use of everolimus in combination with exemestane for the treatment of ER+ HER− advanced breast cancer that have progressed during treatment with either letrozole or anastrozole. However, since then, analysis of the overall survival data has revealed that for this secondary end-point of the study, there was no significant difference between the treatment arms (Piccart et al. 2014). This lack of a robust clinical response could be, as is often the case for PI3K–AKT targeting therapeutics, the result of cellular resistance mechanisms to PI3K–AKT inhibition.

Resistance mechanisms to PI3K–AKT inhibition

Both clinical and pre-clinical studies have identified several different mechanisms by which resistance to PI3K–AKT–mTOR inhibition can arise. These include feedback activation of AKT, increased expression of RTKs and cross-talk with other growth-promoting pathways (reviewed in detail by Thorpe et al. (2015)).

Of particular relevance to the subject of this review, restored FOXO activity, following AKT inhibition, directly mediates the up-regulation of HER3, IGF1R, and insulin RTK gene expression (Chandarlapaty et al. 2011).

Recently, Bihani et al. (2015), investigated the mechanisms of acquired resistance of breast cancer cells to everolimus. The authors demonstrated that breast cancer cell-lines, having acquired everolimus resistance, exhibit bromo domain containing protein 4 (BRD4)-mediated up-regulation of the MYC gene. Up-regulation of MYC expression in ER+ antiestrogen resistance breast cancer cells triggers a pro-survival autophagic adaptation in glucose deprived culture conditions (Shajahan-Haq et al. 2014). As has already been discussed, autophagy appears to be a central player in mechanisms of endocrine resistance. Promisingly, it is possible to pharmacologically inhibit BRD4, and doing so has been shown to overcome the resistance of the cancer cells to mTOR1 inhibition (Bihani et al. 2015).

Concerning the feedback activation of AKT, the Src/c-Abl, multikinase-inhibitor dasatinib, has been shown to effectively block AKT activation following mTOR inhibition in several breast cancer cell lines (Yori et al. 2014). Furthermore, the combination treatment of dasatinib and rapamycin has a synergistic effect upon tumor regression in mouse models, accompanied by a reduction in pulmonary metastasis as well as an increase in time to tumor recurrence (Yori et al. 2014).

Other potential therapeutic targets

Although the targeting of PI3K–AKT still presents the most promising strategy to restore FOXO activity, acquired resistance to PI3K–AKT inhibition currently presents a significant barrier that needs to be overcome. The current trend of trialling combination therapies, whereby PI3K–AKT is inhibited in conjunction with additional molecular targets, may prove effective in maximizing the clinical efficacy of the PI3K inhibitors. Fortunately, the complex cellular regulation of FOXO factors summarized in this review, presents a number of additional molecular targets that could be potentially investigated.

Nuclear export machinery

Nuclear export of FOXOs can be blocked by inhibitors of the 14-3-3 chaperone protein family and related exportins. Dong et al. (2007) demonstrated that treatment of an in vitro leukemia cell-model with the peptide R18, down-regulated 14-3-3 protein expression, which in turn leads to increased nuclear accumulation of FOXO3A; and restored transcription of its anti-proliferative targets p27kip1 and Bim. More recently, Mori et al. (2014) have developed novel compounds that also interact and inhibit the 14-3-3 chaperone proteins, increasing the possibility that eventually some compounds may be suitable for clinical use.

Proteasome

Inhibiting the proteasome-mediated degradation of FOXOs could represent an interesting strategy to restore their cellular levels. However, to date, there are no studies on this topic available in the literature.

FOXOs

Transcription factors are predominantly located in the nucleus and they do not possess enzymatic activity. For these reasons they have historically been considered to be ‘undruggable’ molecular targets. However, a growing number of studies have challenged this assumption. Improved understanding of transcription factor biology, coupled with improved drug design and delivery, make transcription factors attractive and realistic alternative drug targets. This may be particularly useful in clinical scenarios where targeting kinase signaling pathways in cancer cells have met with limited efficacy (Rodon et al. 2013).

Although no examples of directly targeting FOXOs exist, attempts at targeting other members of the FOX family have been reported. Notably, Bhat et al. (2009) identified two thiazole antibiotic compounds, siomycin-A and thiostrepton, that selectively bind to and inhibit the transcriptional activity of the oncogenic FOXM1 protein in in vitro cancer cell-line models. Although the poor water solubility of these compounds (Zhang & Kelly 2012) make them of limited clinical use; nevertheless these observations have propelled a search for other small molecule inhibitors of FOXM1 that can be used safely (Chen et al. 2015b).

A need for caution

It is important to consider that FOXOs are regulators of cellular stress resistance mechanisms, and in at least some circumstances, such treatments may also increase resistance to chemotherapeutics. Therefore, it is crucial to fully characterize FOXO-regulated transcriptional programmes in specific disease-states; to identify those which would be most suitable for targeted reactivation of FOXO tumor suppressor function.

Conclusion

In conclusion, the dysregulation of FOXO factors has emerged as a key molecular feature of endocrine resistance mechanisms. Both pre-clinical and clinical research has shown the promising potential of targeting the PI3K–AKT pathway; as a therapeutic strategy to restore hormone-sensitivity to resistant breast tumors. Furthermore, restoration of FOXO tumor suppressor appears to be a key player in this process. However, PI3K–AKT inhibition may not turn out to be the best approach. As has been discussed, cancer cells can utilize a multitude of different resistance mechanisms to acquire resistance to PI3K–AKT inhibition. Although, preclinical experiments show promising data with regard to blocking PI3K–AKT resistance pathways, it remains to be ascertained whether such strategies will translate into superior clinical efficacy. Therefore, one of the aims of this review was to provide a generalized overview of the multiple interconnected regulatory layers that impact upon FOXO transcriptional activity. Further understanding these processes may identify future molecular targets that can allow clinicians to manipulate FOXOs in a more therapeutically targeted manner.

Declaration of interest

The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

The author is supported by an NHMRC project grant.

Acknowledgements

The author thanks Associate Professor Rory Clifton-Bligh (Kolling Institute of Medical Research, Royal North Shore Hospital) for helpful discussions.

References

  • AdachiMOsawaYUchinamiHKitamuraTAcciliDBrennerDA2007The forkhead transcription factor FoxO1 regulates proliferation and transdifferentiation of hepatic stellate cells. Gastroenterology13214341446. (doi:10.1053/j.gastro.2007.01.033).

  • AokiMJiangHVogtPK2004Proteasomal degradation of the FoxO1 transcriptional regulator in cells transformed by the P3k and Akt oncoproteins. PNAS1011361313617. (doi:10.1073/pnas.0405454101).

  • ArendtLMKuperwasserC2015Form and function: how estrogen and progesterone regulate the mammary epithelial hierarchy. Journal of Mammary Gland Biology and Neoplasia20925. (doi:10.1007/s10911-015-9337-0).

  • ArgirisAWangCXWhalenSGDiGiovannaMP2004Synergistic interactions between tamoxifen and trastuzumab (Herceptin). Clinical Cancer Research1014091420. (doi:10.1158/1078-0432.CCR-1060-02).

  • ArpinoGGreenSJAllredDCLewDMartinoSOsborneCKElledgeRM2004HER-2, amplification, HER-1 expression, and tamoxifen response in estrogen receptor-positive metastatic breast cancer: a Southwest Oncology Group Study. Clinical Cancer Research1056705676. (doi:10.1158/1078-0432.CCR-04-0110).

  • BachelotTBourgierCCropetCRay-CoquardIFerreroJMFreyerGAbadie-LacourtoisieSEymardJCDebledMSpaethD2012Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. Journal of Clinical Oncology3027182724. (doi:10.1200/JCO.2011.39.0708).

  • BanerjiSCibulskisKRangel-EscarenoCBrownKKCarterSLFrederickAMLawrenceMSSivachenkoAYSougnezCZouL2012Sequence analysis of mutations and translocations across breast cancer subtypes. Nature486405409. (doi:10.1038/nature11154).

  • BaselgaJCamponeMPiccartMBurrisHAIIIRugoHSSahmoudTNoguchiSGnantMPritchardKILebrunF2012Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. New England Journal of Medicine366520529. (doi:10.1056/NEJMoa1109653).

  • BergamaschiAKimYHWangPSorlieTHernandez-BoussardTLonningPETibshiraniRBorresen-DaleALPollackJR2006Distinct patterns of DNA copy number alteration are associated with different clinicopathological features and gene-expression subtypes of breast cancer. Genes Chromosomes & Cancer4510331040. (doi:10.1002/gcc.20366).

  • BhatUGHalasiMGartelAL2009Thiazole antibiotics target FoxM1 and induce apoptosis in human cancer cells. PLoS ONE4e5592. (doi:10.1371/journal.pone.0005592).

  • BihaniTEzellSALaddBGrosskurthSEMazzolaAMPietrasMReimerCZindaMFawellSD'CruzCM2015Resistance to everolimus driven by epigenetic regulation of MYC in ER+ breast cancers. Oncotarget624072420. (doi:10.18632/oncotarget.2964).

  • BlancoGHolliKHeikkinenMKallioniemiOPTaskinenP1990Prognostic factors in recurrent breast cancer: relationships to site of recurrence, disease-free interval, female sex steroid receptors, ploidy and histological malignancy grading. British Journal of Cancer62142146. (doi:10.1038/bjc.1990.247).

  • BlissJMKilburnLSColemanREForbesJFCoatesASJonesSEJassemJDelozierTAndersenJParidaensR2012Disease-related outcomes with long-term follow-up: an updated analysis of the intergroup exemestane study. Journal of Clinical Oncology30709717. (doi:10.1200/JCO.2010.33.7899).

  • BorgquistSHolmCStendahlMAnagnostakiLLandbergGJirstromK2008Oestrogen receptors α and β show different associations to clinicopathological parameters and their co-expression might predict a better response to endocrine treatment in breast cancer. Journal of Clinical Pathology61197203. (doi:10.1136/jcp.2006.040378).

  • BrenkmanABde KeizerPLvan den BroekNJJochemsenAGBurgeringBM2008Mdm2 induces mono-ubiquitination of FOXO4. PLoS ONE3e2819. (doi:10.1371/journal.pone.0002819).

  • BriskenC2013Progesterone signalling in breast cancer: a neglected hormone coming into the limelight. Nature Reviews Cancer13385396. (doi:10.1038/nrc3518).

  • BrunetABonniAZigmondMJLinMZJuoPHuLSAndersonMJArdenKCBlenisJGreenbergME1999Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor. Cell96857868. (doi:10.1016/S0092-8674(00)80595-4).

  • BrunetAParkJTranHHuLSHemmingsBAGreenbergME2001Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Molecular and Cellular Biology21952965. (doi:10.1128/MCB.21.3.952-965.2001).

  • BrunetAKanaiFStehnJXuJSarbassovaDFrangioniJVDalalSNDeCaprioJAGreenbergMEYaffeMB200214-3-3 Transits to the nucleus and participates in dynamic nucleocytoplasmic transport. Journal of Cell Biology156817828. (doi:10.1083/jcb.200112059).

  • BunoneGBriandPAMiksicekRJPicardD1996Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. EMBO Journal1521742183.

  • BurnsKAKorachKS2012Estrogen receptors and human disease: an update. Archives of Toxicology8614911504. (doi:10.1007/s00204-012-0868-5).

  • Cancer Genome Atlas NComprehensive molecular portraits of human breast tumoursNature49020126170. (doi:10.1038/nature11412).

  • CastrillonDHMiaoLKolliparaRHornerJWDePinhoRA2003Suppression of ovarian follicle activation in mice by the transcription factor Foxo3a. Science301215218. (doi:10.1126/science.1086336).

  • ChandarlapatySSawaiAScaltritiMRodrik-OutmezguineVGrbovic-HuezoOSerraVMajumderPKBaselgaJRosenN2011AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell195871. (doi:10.1016/j.ccr.2010.10.031).

  • ChenCCaoFBaiLLiuYXieJWangWSiQYangJChangALiuD2015aIKKβ enforces a LIN28B/TCF7L2 positive feedback loop that promotes cancer cell stemness and metastasis. Cancer Research7517251735. (doi:10.1158/0008-5472.CAN-14-2111).

  • ChenYRubenEARajadasJTengNN2015bIn silico investigation of FOXM1 binding and novel inhibitors in epithelial ovarian cancer. Bioorganic & Medicinal Chemistry2345764782. (doi:10.1016/j.bmc.2015.06.002).

  • ChinKDeVriesSFridlyandJSpellmanPTRoydasguptaRKuoWLLapukANeveRMQianZRyderT2006Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell10529541. (doi:10.1016/j.ccr.2006.10.009).

  • ChuBLiuFLiLDingCChenKSunQShenZTanYTanCJiangY2015A benzimidazole derivative exhibiting antitumor activity blocks EGFR and HER2 activity and upregulates DR5 in breast cancer cells. Cell Death & Disease6e1686. (doi:10.1038/cddis.2015.25).

  • ClarkeRCookKL2015Unfolding the role of stress response signaling in endocrine resistant breast cancers. Frontiers in Oncology5140. (doi:10.3389/fonc.2015.00140).

  • ConneelyOMMulac-JericevicBArnett-MansfieldR2007Progesterone signaling in mammary gland development. Ernst Schering Foundation Symposium Proceedings14554. (doi:10.1007/2789_2008_075).

  • CookKLShajahanANWarriAJinLHilakivi-ClarkeLAClarkeR2012Glucose-regulated protein 78 controls cross-talk between apoptosis and autophagy to determine antiestrogen responsiveness. Cancer Research7233373349. (doi:10.1158/0008-5472.CAN-12-0269).

  • CookKLClarkePAParmarJHuRSchwartz-RobertsJLAbu-AsabMWarriABaumannWTClarkeR2014Knockdown of estrogen receptor-α induces autophagy and inhibits antiestrogen-mediated unfolded protein response activation, promoting ROS-induced breast cancer cell death. FASEB Journal2838913905. (doi:10.1096/fj.13-247353).

  • DaitokuHHattaMMatsuzakiHArataniSOhshimaTMiyagishiMNakajimaTFukamizuA2004Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. PNAS1011004210047. (doi:10.1073/pnas.0400593101).

  • DaitokuHSakamakiJFukamizuA2011Regulation of FoxO transcription factors by acetylation and protein–protein interactions. Biochimica et Biophysica Acta181319541960. (doi:10.1016/j.bbamcr.2011.03.001).

  • De LaurentiisMArpinoGMassarelliERuggieroACarlomagnoCCiardielloFTortoraGD'AgostinoDCaputoFCancelloG2005A meta-analysis on the interaction between HER-2 expression and response to endocrine treatment in advanced breast cancer. Clinical Cancer Research1147414748. (doi:10.1158/1078-0432.CCR-04-2569).

  • DerooBJHewittSCCollinsJBGrissomSFHamiltonKJKorachKS2009Profile of estrogen-responsive genes in an estrogen-specific mammary gland outgrowth model. Molecular Reproduction and Development76733750. (doi:10.1002/mrd.21041).

  • DibbleCCCantleyLC2015Regulation of mTORC1 by PI3K signaling. Trends in Cell Biology25545555. (doi:10.1016/j.tcb.2015.06.002).

  • DijkersPFMedemaRHPalsCBanerjiLThomasNSLamEWBurgeringBMRaaijmakersJALammersJWKoendermanL2000Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation of p27(KIP1). Molecular and Cellular Biology2091389148. (doi:10.1128/MCB.20.24.9138-9148.2000).

  • DongSKangSGuTLKardarSFuHLonialSKhouryHJKhuriFChenJ200714-3-3 Integrates prosurvival signals mediated by the AKT and MAPK pathways in ZNF198–FGFR1-transformed hematopoietic cells. Blood110360369. (doi:10.1182/blood-2006-12-065615).

  • EijkelenboomAMokryMde WitESmitsLMPoldermanPEvan TriestMHvan BoxtelRSchulzeAde LaatWCuppenE2013Genome-wide analysis of FOXO3 mediated transcription regulation through RNA polymerase II profiling. Molecular Systems Biology9638. (doi:10.1038/msb.2012.74).

  • EssafiAFernandez de MattosSHassenYASoeiroIMuftiGJThomasNSMedemaRHLamEW2005Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr–Abl-expressing cells. Oncogene2423172329. (doi:10.1038/sj.onc.1208421).

  • EssersMAWeijzenSde Vries-SmitsAMSaarloosIde RuiterNDBosJLBurgeringBM2004FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK. EMBO Journal2348024812. (doi:10.1038/sj.emboj.7600476).

  • FanWMorinagaHKimJJBaeESpannNJHeinzSGlassCKOlefskyJM2010FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages. EMBO Journal2942234236. (doi:10.1038/emboj.2010.268).

  • Fernandez de MattosSEssafiASoeiroIPietersenAMBirkenkampKUEdwardsCSMartinoANelsonBHFrancisJMJonesMC2004FoxO3a and BCR-ABL regulate cyclin D2 transcription through a STAT5/BCL6-dependent mechanism. Molecular and Cellular Biology241005810071. (doi:10.1128/MCB.24.22.10058-10071.2004).

  • FoxEMMillerTWBalkoJMKubaMGSanchezVSmithRALiuSGonzalez-AnguloAMMillsGBYeF2011A kinome-wide screen identifies the insulin/IGF-I receptor pathway as a mechanism of escape from hormone dependence in breast cancer. Cancer Research7167736784. (doi:10.1158/0008-5472.CAN-11-1295).

  • FrogneTBenjaminsenRVSonne-HansenKSorensenBSNexoELaenkholmAVRasmussenLMRieseDJIIde CremouxPStenvangJ2009Activation of ErbB3, EGFR and Erk is essential for growth of human breast cancer cell lines with acquired resistance to fulvestrant. Breast Cancer Research and Treatment114263275. (doi:10.1007/s10549-008-0011-8).

  • FrumanDARommelC2014PI3K and cancer: lessons, challenges and opportunities. Nature Reviews. Drug Discovery13140156. (doi:10.1038/nrd4204).

  • FuWMaQChenLLiPZhangMRamamoorthySNawazZShimojimaTWangHYangY2009MDM2 acts downstream of p53 as an E3 ligase to promote FOXO ubiquitination and degradation. Journal of Biological Chemistry2841398714000. (doi:10.1074/jbc.M901758200).

  • FuruyamaTNakazawaTNakanoIMoriN2000Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues. Biochemical Journal349629634. (doi:10.1042/bj3490629).

  • GajiwalaKSBurleySK2000Winged helix proteins. Current Opinion in Structural Biology10110116. (doi:10.1016/S0959-440X(99)00057-3).

  • GaliliNDavisRJFredericksWJMukhopadhyaySRauscherFJIIIEmanuelBSRoveraGBarrFG1993Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma. Nature Genetics5230235. (doi:10.1038/ng1193-230).

  • GaoJYangXYinPHuWLiaoHMiaoZPanCLiN2012The involvement of FoxO in cell survival and chemosensitivity mediated by Mirk/Dyrk1B in ovarian cancer. International Journal of Oncology4012031209. (doi:10.3892/ijo.2011.1293).

  • GarginiRCerlianiJPEscollMAntonIMWandosellF2015Cancer stem cell-like phenotype and survival are coordinately regulated by Akt/FoxO/Bim pathway. Stem Cells33646660. (doi:10.1002/stem.1904).

  • deGraffenriedLAFriedrichsWERussellDHDonzisEJMiddletonAKSilvaJMRothRAHidalgoM2004Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt Activity. Clinical Cancer Research1080598067. (doi:10.1158/1078-0432.CCR-04-0035).

  • HalacliSODoganAL2015FOXP1 regulation via the PI3K/Akt/p70S6K signaling pathway in breast cancer cells. Oncology Letters914821488. (doi:10.3892/ol.2015.2885).

  • van der HeideLPSmidtMP2005Regulation of FoxO activity by CBP/p300-mediated acetylation. Trends in Biochemical Sciences308186. (doi:10.1016/j.tibs.2004.12.002).

  • HillRCautainBde PedroNLinkW2014aTargeting nucleocytoplasmic transport in cancer therapy. Oncotarget51128. (doi:10.18632/oncotarget.1457).

  • HillRKalathurRKCallejasSColacoLBrandaoRSereldeBCebriaABlanco-AparicioCPastorJFutschikM2014bA novel phosphatidylinositol 3-kinase (PI3K) inhibitor directs a potent FOXO-dependent, p53-independent cell cycle arrest phenotype characterized by the differential induction of a subset of FOXO-regulated genes. Breast Cancer Research16482. (doi:10.1186/s13058-014-0482-y).

  • HoriYSKunoAHosodaRHorioY2013Regulation of FOXOs and p53 by SIRT1 modulators under oxidative stress. PLoS ONE8e73875. (doi:10.1371/journal.pone.0073875).

  • van der HorstAde Vries-SmitsAMBrenkmanABvan TriestMHvan den BroekNCollandFMauriceMMBurgeringBM2006FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP. Nature Cell Biology810641073. (doi:10.1038/ncb1469).

  • HosakaTBiggsWHIIITieuDBoyerADVarkiNMCaveneeWKArdenKC2004Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification. PNAS10129752980. (doi:10.1073/pnas.0400093101).

  • HuMCLeeDFXiaWGolfmanLSOu-YangFYangJYZouYBaoSHanadaNSasoH2004IκB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell117225237. (doi:10.1016/S0092-8674(04)00302-2).

  • HuangHReganKMWangFWangDSmithDIvan DeursenJMTindallDJ2005Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation. PNAS10216491654. (doi:10.1073/pnas.0406789102).

  • ImaeMFuZYoshidaANoguchiTKatoH2003Nutritional and hormonal factors control the gene expression of FoxOs, the mammalian homologues of DAF-16. Journal of Molecular Endocrinology30253262. (doi:10.1677/jme.0.0300253).

  • JacobsFMvan der HeideLPWijchersPJBurbachJPHoekmanMFSmidtMP2003FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics. Journal of Biological Chemistry2783595935967. (doi:10.1074/jbc.M302804200).

  • JacobsKMPenningtonJDBishtKSAykin-BurnsNKimHSMishraMSunLNguyenPAhnBHLeclercJ2008SIRT3 interacts with the daf-16 homolog FOXO3a in the mitochondria, as well as increases FOXO3a dependent gene expression. International Journal of Biological Sciences4291299. (doi:10.7150/ijbs.4.291).

  • JacobsenBMHorwitzKB2012Progesterone receptors, their isoforms and progesterone regulated transcription. Molecular and Cellular Endocrinology3571829. (doi:10.1016/j.mce.2011.09.016).

  • JiaMDahlman-WrightKGustafssonJA2015Estrogen receptor α and β in health and disease. Best Practice & Research. Clinical Endocrinology & Metabolism29557568. (doi:10.1016/j.beem.2015.04.008).

  • JinSPangRPShenJNHuangGWangJZhouJG2007Grifolin induces apoptosis via inhibition of PI3K/AKT signalling pathway in human osteosarcoma cells. Apoptosis1213171326. (doi:10.1007/s10495-007-0062-z).

  • JohnstonSPippenJJrPivotXLichinitserMSadeghiSDierasVGomezHLRomieuGManikhasAKennedyMJ2009Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. Journal of Clinical Oncology2755385546. (doi:10.1200/JCO.2009.23.3734).

  • KatoSEndohHMasuhiroYKitamotoTUchiyamaSSasakiHMasushigeSGotohYNishidaEKawashimaH1995Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science27014911494. (doi:10.1126/science.270.5241.1491).

  • KatohMKatohM2004Human FOX gene family (review). International Journal of Oncology2514951500. (doi:10.3892/ijo.25.5.1495).

  • KaufmanBMackeyJRClemensMRBapsyPPVaidAWardleyATjulandinSJahnMLehleMFeyereislovaA2009Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. Journal of Clinical Oncology2755295537. (doi:10.1200/JCO.2008.20.6847).

  • KirkegaardTWittonCJEdwardsJNielsenKVJensenLBCampbellFMCookeTGBartlettJM2010Molecular alterations in AKT1, AKT2 and AKT3 detected in breast and prostatic cancer by FISH. Histopathology56203211. (doi:10.1111/j.1365-2559.2009.03467.x).

  • KobayashiYFurukawa-HibiYChenCHorioYIsobeKIkedaKMotoyamaN2005SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stress. International Journal of Molecular Medicine16237243. (doi:10.3892/ijmm.16.2.237).

  • LagutinaIConwaySJSublettJGrosveldGC2002Pax3–FKHR knock-in mice show developmental aberrations but do not develop tumors. Molecular and Cellular Biology2272047216. (doi:10.1128/MCB.22.20.7204-7216.2002).

  • LalmansinghASKarmakarSJinYNagaichAK2012Multiple modes of chromatin remodeling by forkhead box proteins. Biochimica et Biophysica Acta1819707715. (doi:10.1016/j.bbagrm.2012.02.018).

  • LamEWFrancisREPetkovicM2006FOXO transcription factors: key regulators of cell fate. Biochemical Society Transactions34722726. (doi:10.1042/BST0340722).

  • LaoukiliJStahlMMedemaRH2007FoxM1: at the crossroads of ageing and cancer. Biochimica et Biophysica Acta177592102. (doi:10.1016/j.bbcan.2006.08.006).

  • LavinskyRMJepsenKHeinzelTTorchiaJMullenTMSchiffRDel-RioALRicoteMNgoSGemschJ1998Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes. PNAS9529202925. (doi:10.1073/pnas.95.6.2920).

  • LeeYRParkJYuHNKimJSYounHJJungSH2005Up-regulation of PI3K/Akt signaling by 17β-estradiol through activation of estrogen receptor-α, but not estrogen receptor-β, and stimulates cell growth in breast cancer cells. Biochemical and Biophysical Research Communications33612211226. (doi:10.1016/j.bbrc.2005.08.256).

  • LehtinenMKYuanZBoagPRYangYVillenJBeckerEBDiBaccoSde la IglesiaNGygiSBlackwellTK2006A conserved MST–FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell1259871001. (doi:10.1016/j.cell.2006.03.046).

  • LiSHanBLiuGLiSOuelletJLabrieFPelletierG2010Immunocytochemical localization of sex steroid hormone receptors in normal human mammary gland. Journal of Histochemistry and Cytochemistry58509515. (doi:10.1369/jhc.2009.954644).

  • LinYCJhunjhunwalaSBennerCHeinzSWelinderEManssonRSigvardssonMHagmanJEspinozaCADutkowskiJ2010A global network of transcription factors, involving E2A, EBF1 and Foxo1, that orchestrates B cell fate. Nature Immunology11635643. (doi:10.1038/ni.1891).

  • LitvakVRatushnyAVLampanoAESchmitzFHuangACRamanARustAGBergthalerAAitchisonJDAderemA2012A FOXO3–IRF7 gene regulatory circuit limits inflammatory sequelae of antiviral responses. Nature490421425. (doi:10.1038/nature11428).

  • LvYSongSZhangKGaoHMaR2013CHIP regulates AKT/FoxO/Bim signaling in MCF7 and MCF10A cells. PLoS ONE8e83312. (doi:10.1371/journal.pone.0083312).

  • MartiniMDe SantisMCBracciniLGulluniFHirschE2014PI3K/AKT signaling pathway and cancer: an updated review. Annals of Medicine46372383. (doi:10.3109/07853890.2014.912836).

  • MatsuzakiHDaitokuHHattaMTanakaKFukamizuA2003Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation. PNAS1001128511290. (doi:10.1073/pnas.1934283100).

  • MatsuzakiHDaitokuHHattaMAoyamaHYoshimochiKFukamizuA2005Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation. PNAS1021127811283. (doi:10.1073/pnas.0502738102).

  • McClaineRJMarshallAMWaghPKWaltzSE2010Ron receptor tyrosine kinase activation confers resistance to tamoxifen in breast cancer cell lines. Neoplasia12650658. (doi:10.1593/neo.10476).

  • MihaylovaMMVasquezDSRavnskjaerKDenechaudPDYuRTAlvarezJGDownesMEvansRMMontminyMShawRJ2011Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose homeostasis. Cell145607621. (doi:10.1016/j.cell.2011.03.043).

  • MillerTWHennessyBTGonzalez-AnguloAMFoxEMMillsGBChenHHighamCGarcia-EcheverriaCShyrYArteagaCL2010Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. Journal of Clinical Investigation12024062413. (doi:10.1172/JCI41680).

  • MillerTWBalkoJMFoxEMGhazouiZDunbierAAndersonHDowsettMJiangASmithRAMairaSM2011ERα-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer. Cancer Discovery1338351. (doi:10.1158/2159-8290.CD-11-0101).

  • ModurVNagarajanREversBMMilbrandtJ2002FOXO proteins regulate tumor necrosis factor-related apoptosis inducing ligand expression. Implications for PTEN mutation in prostate cancer. Journal of Biological Chemistry2774792847937. (doi:10.1074/jbc.M207509200).

  • MontenegroMFCollado-Gonzalez MdelMFernandez-PerezMPHammoudaMBTolordavaLGamkrelidzeMRodriguez-LopezJN2014Promoting E2F1-mediated apoptosis in oestrogen receptor-α-negative breast cancer cells. BMC Cancer14539. (doi:10.1186/1471-2407-14-539).

  • MorelliCLanzinoMGarofaloCMarisPBrunelliECasaburiICatalanoSBrunoRSisciDAndoS2010Akt2 inhibition enables the forkhead transcription factor FoxO3a to have a repressive role in estrogen receptor α transcriptional activity in breast cancer cells. Molecular and Cellular Biology30857870. (doi:10.1128/MCB.00824-09).

  • MoriMVignaroliGCauYDinicJHillRRossiMColecchiaDPesicMLinkWChiarielloM2014Discovery of 14-3-3 protein–protein interaction inhibitors that sensitize multidrug-resistant cancer cells to doxorubicin and the Akt inhibitor GSK690693. ChemMedChem9973983. (doi:10.1002/cmdc.201400044).

  • NowakKKillmerKGessnerCLutzW2007E2F-1 regulates expression of FOXO1 and FOXO3a. Biochimica et Biophysica Acta1769244252. (doi:10.1016/j.bbaexp.2007.04.001).

  • O'HurleyGDalyEO'GradyACumminsRQuinnCFlanaganLPierceAFanYLynnMARaffertyM2014Investigation of molecular alterations of AKT-3 in triple-negative breast cancer. Histopathology64660670. (doi:10.1111/his.12313).

  • OsborneCKSchiffR2011Mechanisms of endocrine resistance in breast cancer. Annual Review of Medicine62233247. (doi:10.1146/annurev-med-070909-182917).

  • PaikJHKolliparaRChuGJiHXiaoYDingZMiaoLTothovaZHornerJWCarrascoDR2007FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell128309323. (doi:10.1016/j.cell.2006.12.029).

  • ParkEGongEYRomanelliMGLeeK2012Suppression of estrogen receptor-α transactivation by thyroid transcription factor-2 in breast cancer cells. Biochemical and Biophysical Research Communications421532537. (doi:10.1016/j.bbrc.2012.04.039).

  • ParryPWeiYEvansG1994Cloning and characterization of the t(X;11) breakpoint from a leukemic cell line identify a new member of the forkhead gene family. Genes Chromosomes & Cancer117984. (doi:10.1002/gcc.2870110203).

  • PearceLRKomanderDAlessiDR2010The nuts and bolts of AGC protein kinases. Nature Reviews. Molecular Cell Biology11922. (doi:10.1038/nrm2822).

  • PerouCM2011Molecular stratification of triple-negative breast cancers. Oncologist16 (Suppl 1) 6170. (doi:10.1634/theoncologist.2011-S1-61).

  • PerouCMSorlieTEisenMBvan de RijnMJeffreySSReesCAPollackJRRossDTJohnsenHAkslenLA2000Molecular portraits of human breast tumours. Nature406747752. (doi:10.1038/35021093).

  • PiccartMHortobagyiGNCamponeMPritchardKILebrunFItoYNoguchiSPerezARugoHSDeleuI2014Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2†. Annals of Oncology2523572362. (doi:10.1093/annonc/mdu456).

  • PlasDRThompsonCB2003Akt activation promotes degradation of tuberin and FOXO3a via the proteasome. Journal of Biological Chemistry2781236112366. (doi:10.1074/jbc.M213069200).

  • PotenteMUrbichCSasakiKHofmannWKHeeschenCAicherAKolliparaRDePinhoRAZeiherAMDimmelerS2005Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization. Journal of Clinical Investigation11523822392. (doi:10.1172/JCI23126).

  • PritchardKIBurrisHAIIIItoYRugoHSDakhilSHortobagyiGNCamponeMCsosziTBaselgaJPuttawibulP2013Safety and efficacy of everolimus with exemestane vs. exemestane alone in elderly patients with HER2-negative, hormone receptor-positive breast cancer in BOLERO-2. Clinical Breast Cancer13421432.e8. (doi:10.1016/j.clbc.2013.08.011).

  • RenaGWoodsYLPrescottARPeggieMUntermanTGWilliamsMRCohenP2002Two novel phosphorylation sites on FKHR that are critical for its nuclear exclusion. EMBO Journal2122632271. (doi:10.1093/emboj/21.9.2263).

  • RodonJDienstmannRSerraVTaberneroJ2013Development of PI3K inhibitors: lessons learned from early clinical trials. Nature Reviews. Clinical Oncology10143153. (doi:10.1038/nrclinonc.2013.10).

  • RugoHSDosing and safety implications for oncologists when administering everolimus to patients with hormone receptor-positive breast cancerClinical Breast Cancer2015[in press]doi:10.1016/j.clbc.2015.09.004).

  • Schmitt-NeyMCamussiG2015The PAX3–FOXO1 fusion protein present in rhabdomyosarcoma interferes with normal FOXO activity and the TGF-β pathway. PLoS ONE10e0121474. (doi:10.1371/journal.pone.0121474).

  • SchuurERLoktevAVSharmaMSunZRothRAWeigelRJ2001Ligand-dependent interaction of estrogen receptor-α with members of the forkhead transcription factor family. Journal of Biological Chemistry2763355433560. (doi:10.1074/jbc.M105555200).

  • Seton-RogersS2015Breast cancer: untangling the role of progesterone receptors. Nature Reviews. Cancer15456. (doi:10.1038/nrc3991).

  • Shajahan-HaqANCookKLSchwartz-RobertsJLEltayebAEDemasDMWarriAMFaceyCOHilakivi-ClarkeLAClarkeR2014MYC regulates the unfolded protein response and glucose and glutamine uptake in endocrine resistant breast cancer. Molecular Cell13239. (doi:10.1186/1476-4598-13-239).

  • ShangYBrownM2002Molecular determinants for the tissue specificity of SERMs. Science29524652468. (doi:10.1126/science.1068537).

  • ShangYHuXDiRenzoJLazarMABrownM2000Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription. Cell103843852. (doi:10.1016/S0092-8674(00)00188-4).

  • SiegelRWardEBrawleyOJemalA2011Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA: A Cancer Journal for Clinicians61212236. (doi:10.3322/caac.20121).

  • SimonciniTHafezi-MoghadamABrazilDPLeyKChinWWLiaoJK2000Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature407538541. (doi:10.1038/35035131).

  • SisciDMarisPCesarioMGAnselmoWCoronitiRTrombinoGERomeoFFerraroALanzinoMAquilaS2013The estrogen receptor α is the key regulator of the bifunctional role of FoxO3a transcription factor in breast cancer motility and invasiveness. Cell Cycle1234053420. (doi:10.4161/cc.26421).

  • StalOPerez-TenorioGAkerbergLOlssonBNordenskjoldBSkoogLRutqvistLE2003Akt kinases in breast cancer and the results of adjuvant therapy. Breast Cancer Research5R37R44. (doi:10.1186/bcr569).

  • SublettJEJeonISShapiroDN1995The alveolar rhabdomyosarcoma PAX3/FKHR fusion protein is a transcriptional activator. Oncogene11545552.

  • SundaresanNRGuptaMKimGRajamohanSBIsbatanAGuptaMP2009Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. Journal of Clinical Investigation11927582771. (doi:10.1172/JCI39162).

  • ThorpeLMYuzugulluHZhaoJJ2015PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nature Reviews. Cancer15724. (doi:10.1038/nrc3860).

  • TokunagaEKimuraYOkiEUedaNFutatsugiMMashinoKYamamotoMIkebeMKakejiYBabaH2006Akt is frequently activated in HER2/neu-positive breast cancers and associated with poor prognosis among hormone-treated patients. International Journal of Cancer118284289. (doi:10.1002/ijc.21358).

  • TokunagaEHisamatsuYTanakaKYamashitaNSaekiHOkiEKitaoHMaeharaY2014Molecular mechanisms regulating the hormone sensitivity of breast cancer. Cancer Science10513771383. (doi:10.1111/cas.12521).

  • TurnerNPearsonASharpeRLambrosMGeyerFLopez-GarciaMANatrajanRMarchioCIornsEMackayA2010FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Research7020852094. (doi:10.1158/0008-5472.CAN-09-3746).

  • TzaharEWatermanHChenXLevkowitzGKarunagaranDLaviSRatzkinBJYardenY1996A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Molecular and Cellular Biology1652765287. (doi:10.1128/MCB.16.10.5276).

  • WangCXKoayDCEdwardsALuZMorGOcalITDigiovannaMP2005In vitro and in vivo effects of combination of trastuzumab (Herceptin) and tamoxifen in breast cancer. Breast Cancer Research and Treatment92251263. (doi:10.1007/s10549-005-3375-z).

  • WangFMarshallCBYamamotoKLiGYPlevinMJYouHMakTWIkuraM2008Biochemical and structural characterization of an intramolecular interaction in FOXO3a and its binding with p53. Journal of Molecular Biology384590603. (doi:10.1016/j.jmb.2008.09.025).

  • WangFMarshallCBLiGYYamamotoKMakTWIkuraM2009Synergistic interplay between promoter recognition and CBP/p300 coactivator recruitment by FOXO3a. ACS Chemical Biology410171027. (doi:10.1021/cb900190u).

  • WangFMarshallCBYamamotoKLiGYGasmi-SeabrookGMOkadaHMakTWIkuraM2012aStructures of KIX domain of CBP in complex with two FOXO3a transactivation domains reveal promiscuity and plasticity in coactivator recruitment. PNAS10960786083. (doi:10.1073/pnas.1119073109).

  • WangFChanCHChenKGuanXLinHKTongQ2012bDeacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation. Oncogene3115461557. (doi:10.1038/onc.2011.347).

  • WangYQCaoQWangFHuangLYSangTTLiuFChenSY2015SIRT1 protects against oxidative stress-induced endothelial progenitor cells apoptosis by inhibiting FOXO3a via FOXO3a ubiquitination and degradation. Journal of Cellular Physiology23020982107. (doi:10.1002/jcp.24938).

  • WebbAEBrunetA2014FOXO transcription factors: key regulators of cellular quality control. Trends in Biochemical Sciences39159169. (doi:10.1016/j.tibs.2014.02.003).

  • WeigelDJackleH1990The fork head domain: a novel DNA binding motif of eukaryotic transcription factors?Cell63455456. (doi:10.1016/0092-8674(90)90439-L).

  • WeigelDJurgensGKuttnerFSeifertEJackleH1989The homeotic gene fork head encodes a nuclear protein and is expressed in the terminal regions of the Drosophila embryo. Cell57645658. (doi:10.1016/0092-8674(89)90133-5).

  • WijchersPJBurbachJPSmidtMP2006In control of biology: of mice, men and Foxes. Biochemical Journal397233246. (doi:10.1042/BJ20060387).

  • WondisfordARXiongLChangEMengSMeyersDJLiMColePAHeL2014Control of Foxo1 gene expression by co-activator P300. Journal of Biological Chemistry28943264333. (doi:10.1074/jbc.M113.540500).

  • WrightTMWardellSEJasperJSSticeJPSafiRNelsonERMcDonnellDP2014Delineation of a FOXA1/ERα/AGR2 regulatory loop that is dysregulated in endocrine therapy-resistant breast cancer. Molecular Cancer Research1218291839. (doi:10.1158/1541-7786.MCR-14-0195).

  • YangJYZongCSXiaWYamaguchiHDingQXieXLangJYLaiCCChangCJHuangWC2008ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nature Cell Biology10138148. (doi:10.1038/ncb1676).

  • YardleyDANoguchiSPritchardKIBurrisHAIIIBaselgaJGnantMHortobagyiGNCamponeMPistilliBPiccartM2013Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Advances in Therapy30870884. (doi:10.1007/s12325-013-0060-1).

  • YoriJLLozadaKLSeachristDDMosleyJDAbdul-KarimFWBoothCNFlaskCAKeriRA2014Combined SFK/mTOR inhibition prevents rapamycin-induced feedback activation of AKT and elicits efficient tumor regression. Cancer Research7447624771. (doi:10.1158/0008-5472.CAN-13-3627).

  • YuanZBeckerEBMerloPYamadaTDiBaccoSKonishiYSchaeferEMBonniA2008Activation of FOXO1 by Cdk1 in cycling cells and postmitotic neurons. Science31916651668. (doi:10.1126/science.1152337).

  • ZhangFKellyWL2012In vivo production of thiopeptide variants. Methods in Enzymology516324. (doi:10.1016/B978-0-12-394291-3.00022-8).

  • ZhangYGanBLiuDPaikJH2011FoxO family members in cancer. Cancer Biology & Therapy12253259. (doi:10.4161/cbt.12.4.15954).

  • ZhaoHHHerreraRECoronado-HeinsohnEYangMCLudes-MeyersJHSeybold-TilsonKJNawazZYeeDBarrFGDiabSG2001Forkhead homologue in rhabdomyosarcoma functions as a bifunctional nuclear receptor-interacting protein with both coactivator and corepressor functions. Journal of Biological Chemistry2762790727912. (doi:10.1074/jbc.M104278200).

  • ZhouXTanMStone HawthorneVKlosKSLanKHYangYYangWSmithTLShiDYuD2004Activation of the Akt/mammalian target of rapamycin/4E-BP1 pathway by ErbB2 overexpression predicts tumor progression in breast cancers. Clinical Cancer Research1067796788. (doi:10.1158/1078-0432.CCR-04-0112).

  • ZieglerSF2006FOXP3: of mice and men. Annual Review of Immunology24209226. (doi:10.1146/annurev.immunol.24.021605.090547).

  • ZouYTsaiWBChengCJHsuCChungYMLiPCLinSHHuMC2008Forkhead box transcription factor FOXO3a suppresses estrogen-dependent breast cancer cell proliferation and tumorigenesis. Breast Cancer Research10R21. (doi:10.1186/bcr1872).

If the inline PDF is not rendering correctly, you can download the PDF file here.

 

      Society for Endocrinology

Related Articles

Article Information

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 1173 1173 227
PDF Downloads 195 195 25

Altmetrics

Figures

  • View in gallery

    Genetic changes found in different forms of breast cancer that cause chronic activation of the PI3K–AKT pathway. Afflicted components of the pathway are highlighted, and the specific nature of the most common mutations described: (1) HER2 receptor amplification; (2) PI3CA (p110) activating mutations; (3) deletion of INPP4B gene; (4) PTEN inactivating mutations/deletions; and (5) AKT1/AKT3 activating mutations.

  • View in gallery

    Location of post-translational modifications that regulate FOXO transcriptional activity. A schematic representation of the four members of the human FOXO family are shown with amino-acid positions of important structural features and modifications highlighted.

  • View in gallery

    Potential therapeutic targets that could be used to restore FOXO signaling activity in breast cancer cells: (1) kinase signaling pathways that promote nuclear export and sequestration of FOXOs in the cytoplasm; (2) chaperone proteins such as 14-3-3 and exportins; (3) proteasomal degradation of FOXOs; and (4) FOXO interaction with DNA-promoter targets and transcriptional machinery.

References

AdachiMOsawaYUchinamiHKitamuraTAcciliDBrennerDA2007The forkhead transcription factor FoxO1 regulates proliferation and transdifferentiation of hepatic stellate cells. Gastroenterology13214341446. (doi:10.1053/j.gastro.2007.01.033).

AokiMJiangHVogtPK2004Proteasomal degradation of the FoxO1 transcriptional regulator in cells transformed by the P3k and Akt oncoproteins. PNAS1011361313617. (doi:10.1073/pnas.0405454101).

ArendtLMKuperwasserC2015Form and function: how estrogen and progesterone regulate the mammary epithelial hierarchy. Journal of Mammary Gland Biology and Neoplasia20925. (doi:10.1007/s10911-015-9337-0).

ArgirisAWangCXWhalenSGDiGiovannaMP2004Synergistic interactions between tamoxifen and trastuzumab (Herceptin). Clinical Cancer Research1014091420. (doi:10.1158/1078-0432.CCR-1060-02).

ArpinoGGreenSJAllredDCLewDMartinoSOsborneCKElledgeRM2004HER-2, amplification, HER-1 expression, and tamoxifen response in estrogen receptor-positive metastatic breast cancer: a Southwest Oncology Group Study. Clinical Cancer Research1056705676. (doi:10.1158/1078-0432.CCR-04-0110).

BachelotTBourgierCCropetCRay-CoquardIFerreroJMFreyerGAbadie-LacourtoisieSEymardJCDebledMSpaethD2012Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. Journal of Clinical Oncology3027182724. (doi:10.1200/JCO.2011.39.0708).

BanerjiSCibulskisKRangel-EscarenoCBrownKKCarterSLFrederickAMLawrenceMSSivachenkoAYSougnezCZouL2012Sequence analysis of mutations and translocations across breast cancer subtypes. Nature486405409. (doi:10.1038/nature11154).

BaselgaJCamponeMPiccartMBurrisHAIIIRugoHSSahmoudTNoguchiSGnantMPritchardKILebrunF2012Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. New England Journal of Medicine366520529. (doi:10.1056/NEJMoa1109653).

BergamaschiAKimYHWangPSorlieTHernandez-BoussardTLonningPETibshiraniRBorresen-DaleALPollackJR2006Distinct patterns of DNA copy number alteration are associated with different clinicopathological features and gene-expression subtypes of breast cancer. Genes Chromosomes & Cancer4510331040. (doi:10.1002/gcc.20366).

BhatUGHalasiMGartelAL2009Thiazole antibiotics target FoxM1 and induce apoptosis in human cancer cells. PLoS ONE4e5592. (doi:10.1371/journal.pone.0005592).

BihaniTEzellSALaddBGrosskurthSEMazzolaAMPietrasMReimerCZindaMFawellSD'CruzCM2015Resistance to everolimus driven by epigenetic regulation of MYC in ER+ breast cancers. Oncotarget624072420. (doi:10.18632/oncotarget.2964).

BlancoGHolliKHeikkinenMKallioniemiOPTaskinenP1990Prognostic factors in recurrent breast cancer: relationships to site of recurrence, disease-free interval, female sex steroid receptors, ploidy and histological malignancy grading. British Journal of Cancer62142146. (doi:10.1038/bjc.1990.247).

BlissJMKilburnLSColemanREForbesJFCoatesASJonesSEJassemJDelozierTAndersenJParidaensR2012Disease-related outcomes with long-term follow-up: an updated analysis of the intergroup exemestane study. Journal of Clinical Oncology30709717. (doi:10.1200/JCO.2010.33.7899).

BorgquistSHolmCStendahlMAnagnostakiLLandbergGJirstromK2008Oestrogen receptors α and β show different associations to clinicopathological parameters and their co-expression might predict a better response to endocrine treatment in breast cancer. Journal of Clinical Pathology61197203. (doi:10.1136/jcp.2006.040378).

BrenkmanABde KeizerPLvan den BroekNJJochemsenAGBurgeringBM2008Mdm2 induces mono-ubiquitination of FOXO4. PLoS ONE3e2819. (doi:10.1371/journal.pone.0002819).

BriskenC2013Progesterone signalling in breast cancer: a neglected hormone coming into the limelight. Nature Reviews Cancer13385396. (doi:10.1038/nrc3518).

BrunetABonniAZigmondMJLinMZJuoPHuLSAndersonMJArdenKCBlenisJGreenbergME1999Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor. Cell96857868. (doi:10.1016/S0092-8674(00)80595-4).

BrunetAParkJTranHHuLSHemmingsBAGreenbergME2001Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Molecular and Cellular Biology21952965. (doi:10.1128/MCB.21.3.952-965.2001).

BrunetAKanaiFStehnJXuJSarbassovaDFrangioniJVDalalSNDeCaprioJAGreenbergMEYaffeMB200214-3-3 Transits to the nucleus and participates in dynamic nucleocytoplasmic transport. Journal of Cell Biology156817828. (doi:10.1083/jcb.200112059).

BunoneGBriandPAMiksicekRJPicardD1996Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. EMBO Journal1521742183.

BurnsKAKorachKS2012Estrogen receptors and human disease: an update. Archives of Toxicology8614911504. (doi:10.1007/s00204-012-0868-5).

Cancer Genome Atlas NComprehensive molecular portraits of human breast tumoursNature49020126170. (doi:10.1038/nature11412).

CastrillonDHMiaoLKolliparaRHornerJWDePinhoRA2003Suppression of ovarian follicle activation in mice by the transcription factor Foxo3a. Science301215218. (doi:10.1126/science.1086336).

ChandarlapatySSawaiAScaltritiMRodrik-OutmezguineVGrbovic-HuezoOSerraVMajumderPKBaselgaJRosenN2011AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell195871. (doi:10.1016/j.ccr.2010.10.031).

ChenCCaoFBaiLLiuYXieJWangWSiQYangJChangALiuD2015aIKKβ enforces a LIN28B/TCF7L2 positive feedback loop that promotes cancer cell stemness and metastasis. Cancer Research7517251735. (doi:10.1158/0008-5472.CAN-14-2111).

ChenYRubenEARajadasJTengNN2015bIn silico investigation of FOXM1 binding and novel inhibitors in epithelial ovarian cancer. Bioorganic & Medicinal Chemistry2345764782. (doi:10.1016/j.bmc.2015.06.002).

ChinKDeVriesSFridlyandJSpellmanPTRoydasguptaRKuoWLLapukANeveRMQianZRyderT2006Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell10529541. (doi:10.1016/j.ccr.2006.10.009).

ChuBLiuFLiLDingCChenKSunQShenZTanYTanCJiangY2015A benzimidazole derivative exhibiting antitumor activity blocks EGFR and HER2 activity and upregulates DR5 in breast cancer cells. Cell Death & Disease6e1686. (doi:10.1038/cddis.2015.25).

ClarkeRCookKL2015Unfolding the role of stress response signaling in endocrine resistant breast cancers. Frontiers in Oncology5140. (doi:10.3389/fonc.2015.00140).

ConneelyOMMulac-JericevicBArnett-MansfieldR2007Progesterone signaling in mammary gland development. Ernst Schering Foundation Symposium Proceedings14554. (doi:10.1007/2789_2008_075).

CookKLShajahanANWarriAJinLHilakivi-ClarkeLAClarkeR2012Glucose-regulated protein 78 controls cross-talk between apoptosis and autophagy to determine antiestrogen responsiveness. Cancer Research7233373349. (doi:10.1158/0008-5472.CAN-12-0269).

CookKLClarkePAParmarJHuRSchwartz-RobertsJLAbu-AsabMWarriABaumannWTClarkeR2014Knockdown of estrogen receptor-α induces autophagy and inhibits antiestrogen-mediated unfolded protein response activation, promoting ROS-induced breast cancer cell death. FASEB Journal2838913905. (doi:10.1096/fj.13-247353).

DaitokuHHattaMMatsuzakiHArataniSOhshimaTMiyagishiMNakajimaTFukamizuA2004Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. PNAS1011004210047. (doi:10.1073/pnas.0400593101).

DaitokuHSakamakiJFukamizuA2011Regulation of FoxO transcription factors by acetylation and protein–protein interactions. Biochimica et Biophysica Acta181319541960. (doi:10.1016/j.bbamcr.2011.03.001).

De LaurentiisMArpinoGMassarelliERuggieroACarlomagnoCCiardielloFTortoraGD'AgostinoDCaputoFCancelloG2005A meta-analysis on the interaction between HER-2 expression and response to endocrine treatment in advanced breast cancer. Clinical Cancer Research1147414748. (doi:10.1158/1078-0432.CCR-04-2569).

DerooBJHewittSCCollinsJBGrissomSFHamiltonKJKorachKS2009Profile of estrogen-responsive genes in an estrogen-specific mammary gland outgrowth model. Molecular Reproduction and Development76733750. (doi:10.1002/mrd.21041).

DibbleCCCantleyLC2015Regulation of mTORC1 by PI3K signaling. Trends in Cell Biology25545555. (doi:10.1016/j.tcb.2015.06.002).

DijkersPFMedemaRHPalsCBanerjiLThomasNSLamEWBurgeringBMRaaijmakersJALammersJWKoendermanL2000Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation of p27(KIP1). Molecular and Cellular Biology2091389148. (doi:10.1128/MCB.20.24.9138-9148.2000).

DongSKangSGuTLKardarSFuHLonialSKhouryHJKhuriFChenJ200714-3-3 Integrates prosurvival signals mediated by the AKT and MAPK pathways in ZNF198–FGFR1-transformed hematopoietic cells. Blood110360369. (doi:10.1182/blood-2006-12-065615).

EijkelenboomAMokryMde WitESmitsLMPoldermanPEvan TriestMHvan BoxtelRSchulzeAde LaatWCuppenE2013Genome-wide analysis of FOXO3 mediated transcription regulation through RNA polymerase II profiling. Molecular Systems Biology9638. (doi:10.1038/msb.2012.74).

EssafiAFernandez de MattosSHassenYASoeiroIMuftiGJThomasNSMedemaRHLamEW2005Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr–Abl-expressing cells. Oncogene2423172329. (doi:10.1038/sj.onc.1208421).

EssersMAWeijzenSde Vries-SmitsAMSaarloosIde RuiterNDBosJLBurgeringBM2004FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK. EMBO Journal2348024812. (doi:10.1038/sj.emboj.7600476).

FanWMorinagaHKimJJBaeESpannNJHeinzSGlassCKOlefskyJM2010FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages. EMBO Journal2942234236. (doi:10.1038/emboj.2010.268).

Fernandez de MattosSEssafiASoeiroIPietersenAMBirkenkampKUEdwardsCSMartinoANelsonBHFrancisJMJonesMC2004FoxO3a and BCR-ABL regulate cyclin D2 transcription through a STAT5/BCL6-dependent mechanism. Molecular and Cellular Biology241005810071. (doi:10.1128/MCB.24.22.10058-10071.2004).

FoxEMMillerTWBalkoJMKubaMGSanchezVSmithRALiuSGonzalez-AnguloAMMillsGBYeF2011A kinome-wide screen identifies the insulin/IGF-I receptor pathway as a mechanism of escape from hormone dependence in breast cancer. Cancer Research7167736784. (doi:10.1158/0008-5472.CAN-11-1295).

FrogneTBenjaminsenRVSonne-HansenKSorensenBSNexoELaenkholmAVRasmussenLMRieseDJIIde CremouxPStenvangJ2009Activation of ErbB3, EGFR and Erk is essential for growth of human breast cancer cell lines with acquired resistance to fulvestrant. Breast Cancer Research and Treatment114263275. (doi:10.1007/s10549-008-0011-8).

FrumanDARommelC2014PI3K and cancer: lessons, challenges and opportunities. Nature Reviews. Drug Discovery13140156. (doi:10.1038/nrd4204).

FuWMaQChenLLiPZhangMRamamoorthySNawazZShimojimaTWangHYangY2009MDM2 acts downstream of p53 as an E3 ligase to promote FOXO ubiquitination and degradation. Journal of Biological Chemistry2841398714000. (doi:10.1074/jbc.M901758200).

FuruyamaTNakazawaTNakanoIMoriN2000Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues. Biochemical Journal349629634. (doi:10.1042/bj3490629).

GajiwalaKSBurleySK2000Winged helix proteins. Current Opinion in Structural Biology10110116. (doi:10.1016/S0959-440X(99)00057-3).

GaliliNDavisRJFredericksWJMukhopadhyaySRauscherFJIIIEmanuelBSRoveraGBarrFG1993Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma. Nature Genetics5230235. (doi:10.1038/ng1193-230).

GaoJYangXYinPHuWLiaoHMiaoZPanCLiN2012The involvement of FoxO in cell survival and chemosensitivity mediated by Mirk/Dyrk1B in ovarian cancer. International Journal of Oncology4012031209. (doi:10.3892/ijo.2011.1293).

GarginiRCerlianiJPEscollMAntonIMWandosellF2015Cancer stem cell-like phenotype and survival are coordinately regulated by Akt/FoxO/Bim pathway. Stem Cells33646660. (doi:10.1002/stem.1904).

deGraffenriedLAFriedrichsWERussellDHDonzisEJMiddletonAKSilvaJMRothRAHidalgoM2004Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt Activity. Clinical Cancer Research1080598067. (doi:10.1158/1078-0432.CCR-04-0035).

HalacliSODoganAL2015FOXP1 regulation via the PI3K/Akt/p70S6K signaling pathway in breast cancer cells. Oncology Letters914821488. (doi:10.3892/ol.2015.2885).

van der HeideLPSmidtMP2005Regulation of FoxO activity by CBP/p300-mediated acetylation. Trends in Biochemical Sciences308186. (doi:10.1016/j.tibs.2004.12.002).

HillRCautainBde PedroNLinkW2014aTargeting nucleocytoplasmic transport in cancer therapy. Oncotarget51128. (doi:10.18632/oncotarget.1457).

HillRKalathurRKCallejasSColacoLBrandaoRSereldeBCebriaABlanco-AparicioCPastorJFutschikM2014bA novel phosphatidylinositol 3-kinase (PI3K) inhibitor directs a potent FOXO-dependent, p53-independent cell cycle arrest phenotype characterized by the differential induction of a subset of FOXO-regulated genes. Breast Cancer Research16482. (doi:10.1186/s13058-014-0482-y).

HoriYSKunoAHosodaRHorioY2013Regulation of FOXOs and p53 by SIRT1 modulators under oxidative stress. PLoS ONE8e73875. (doi:10.1371/journal.pone.0073875).

van der HorstAde Vries-SmitsAMBrenkmanABvan TriestMHvan den BroekNCollandFMauriceMMBurgeringBM2006FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP. Nature Cell Biology810641073. (doi:10.1038/ncb1469).

HosakaTBiggsWHIIITieuDBoyerADVarkiNMCaveneeWKArdenKC2004Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification. PNAS10129752980. (doi:10.1073/pnas.0400093101).

HuMCLeeDFXiaWGolfmanLSOu-YangFYangJYZouYBaoSHanadaNSasoH2004IκB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell117225237. (doi:10.1016/S0092-8674(04)00302-2).

HuangHReganKMWangFWangDSmithDIvan DeursenJMTindallDJ2005Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation. PNAS10216491654. (doi:10.1073/pnas.0406789102).

ImaeMFuZYoshidaANoguchiTKatoH2003Nutritional and hormonal factors control the gene expression of FoxOs, the mammalian homologues of DAF-16. Journal of Molecular Endocrinology30253262. (doi:10.1677/jme.0.0300253).

JacobsFMvan der HeideLPWijchersPJBurbachJPHoekmanMFSmidtMP2003FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics. Journal of Biological Chemistry2783595935967. (doi:10.1074/jbc.M302804200).

JacobsKMPenningtonJDBishtKSAykin-BurnsNKimHSMishraMSunLNguyenPAhnBHLeclercJ2008SIRT3 interacts with the daf-16 homolog FOXO3a in the mitochondria, as well as increases FOXO3a dependent gene expression. International Journal of Biological Sciences4291299. (doi:10.7150/ijbs.4.291).

JacobsenBMHorwitzKB2012Progesterone receptors, their isoforms and progesterone regulated transcription. Molecular and Cellular Endocrinology3571829. (doi:10.1016/j.mce.2011.09.016).

JiaMDahlman-WrightKGustafssonJA2015Estrogen receptor α and β in health and disease. Best Practice & Research. Clinical Endocrinology & Metabolism29557568. (doi:10.1016/j.beem.2015.04.008).

JinSPangRPShenJNHuangGWangJZhouJG2007Grifolin induces apoptosis via inhibition of PI3K/AKT signalling pathway in human osteosarcoma cells. Apoptosis1213171326. (doi:10.1007/s10495-007-0062-z).

JohnstonSPippenJJrPivotXLichinitserMSadeghiSDierasVGomezHLRomieuGManikhasAKennedyMJ2009Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. Journal of Clinical Oncology2755385546. (doi:10.1200/JCO.2009.23.3734).

KatoSEndohHMasuhiroYKitamotoTUchiyamaSSasakiHMasushigeSGotohYNishidaEKawashimaH1995Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science27014911494. (doi:10.1126/science.270.5241.1491).

KatohMKatohM2004Human FOX gene family (review). International Journal of Oncology2514951500. (doi:10.3892/ijo.25.5.1495).

KaufmanBMackeyJRClemensMRBapsyPPVaidAWardleyATjulandinSJahnMLehleMFeyereislovaA2009Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. Journal of Clinical Oncology2755295537. (doi:10.1200/JCO.2008.20.6847).

KirkegaardTWittonCJEdwardsJNielsenKVJensenLBCampbellFMCookeTGBartlettJM2010Molecular alterations in AKT1, AKT2 and AKT3 detected in breast and prostatic cancer by FISH. Histopathology56203211. (doi:10.1111/j.1365-2559.2009.03467.x).

KobayashiYFurukawa-HibiYChenCHorioYIsobeKIkedaKMotoyamaN2005SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stress. International Journal of Molecular Medicine16237243. (doi:10.3892/ijmm.16.2.237).

LagutinaIConwaySJSublettJGrosveldGC2002Pax3–FKHR knock-in mice show developmental aberrations but do not develop tumors. Molecular and Cellular Biology2272047216. (doi:10.1128/MCB.22.20.7204-7216.2002).

LalmansinghASKarmakarSJinYNagaichAK2012Multiple modes of chromatin remodeling by forkhead box proteins. Biochimica et Biophysica Acta1819707715. (doi:10.1016/j.bbagrm.2012.02.018).

LamEWFrancisREPetkovicM2006FOXO transcription factors: key regulators of cell fate. Biochemical Society Transactions34722726. (doi:10.1042/BST0340722).

LaoukiliJStahlMMedemaRH2007FoxM1: at the crossroads of ageing and cancer. Biochimica et Biophysica Acta177592102. (doi:10.1016/j.bbcan.2006.08.006).

LavinskyRMJepsenKHeinzelTTorchiaJMullenTMSchiffRDel-RioALRicoteMNgoSGemschJ1998Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes. PNAS9529202925. (doi:10.1073/pnas.95.6.2920).

LeeYRParkJYuHNKimJSYounHJJungSH2005Up-regulation of PI3K/Akt signaling by 17β-estradiol through activation of estrogen receptor-α, but not estrogen receptor-β, and stimulates cell growth in breast cancer cells. Biochemical and Biophysical Research Communications33612211226. (doi:10.1016/j.bbrc.2005.08.256).

LehtinenMKYuanZBoagPRYangYVillenJBeckerEBDiBaccoSde la IglesiaNGygiSBlackwellTK2006A conserved MST–FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell1259871001. (doi:10.1016/j.cell.2006.03.046).

LiSHanBLiuGLiSOuelletJLabrieFPelletierG2010Immunocytochemical localization of sex steroid hormone receptors in normal human mammary gland. Journal of Histochemistry and Cytochemistry58509515. (doi:10.1369/jhc.2009.954644).

LinYCJhunjhunwalaSBennerCHeinzSWelinderEManssonRSigvardssonMHagmanJEspinozaCADutkowskiJ2010A global network of transcription factors, involving E2A, EBF1 and Foxo1, that orchestrates B cell fate. Nature Immunology11635643. (doi:10.1038/ni.1891).

LitvakVRatushnyAVLampanoAESchmitzFHuangACRamanARustAGBergthalerAAitchisonJDAderemA2012A FOXO3–IRF7 gene regulatory circuit limits inflammatory sequelae of antiviral responses. Nature490421425. (doi:10.1038/nature11428).

LvYSongSZhangKGaoHMaR2013CHIP regulates AKT/FoxO/Bim signaling in MCF7 and MCF10A cells. PLoS ONE8e83312. (doi:10.1371/journal.pone.0083312).

MartiniMDe SantisMCBracciniLGulluniFHirschE2014PI3K/AKT signaling pathway and cancer: an updated review. Annals of Medicine46372383. (doi:10.3109/07853890.2014.912836).

MatsuzakiHDaitokuHHattaMTanakaKFukamizuA2003Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation. PNAS1001128511290. (doi:10.1073/pnas.1934283100).

MatsuzakiHDaitokuHHattaMAoyamaHYoshimochiKFukamizuA2005Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation. PNAS1021127811283. (doi:10.1073/pnas.0502738102).

McClaineRJMarshallAMWaghPKWaltzSE2010Ron receptor tyrosine kinase activation confers resistance to tamoxifen in breast cancer cell lines. Neoplasia12650658. (doi:10.1593/neo.10476).

MihaylovaMMVasquezDSRavnskjaerKDenechaudPDYuRTAlvarezJGDownesMEvansRMMontminyMShawRJ2011Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose homeostasis. Cell145607621. (doi:10.1016/j.cell.2011.03.043).

MillerTWHennessyBTGonzalez-AnguloAMFoxEMMillsGBChenHHighamCGarcia-EcheverriaCShyrYArteagaCL2010Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. Journal of Clinical Investigation12024062413. (doi:10.1172/JCI41680).

MillerTWBalkoJMFoxEMGhazouiZDunbierAAndersonHDowsettMJiangASmithRAMairaSM2011ERα-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer. Cancer Discovery1338351. (doi:10.1158/2159-8290.CD-11-0101).

ModurVNagarajanREversBMMilbrandtJ2002FOXO proteins regulate tumor necrosis factor-related apoptosis inducing ligand expression. Implications for PTEN mutation in prostate cancer. Journal of Biological Chemistry2774792847937. (doi:10.1074/jbc.M207509200).

MontenegroMFCollado-Gonzalez MdelMFernandez-PerezMPHammoudaMBTolordavaLGamkrelidzeMRodriguez-LopezJN2014Promoting E2F1-mediated apoptosis in oestrogen receptor-α-negative breast cancer cells. BMC Cancer14539. (doi:10.1186/1471-2407-14-539).

MorelliCLanzinoMGarofaloCMarisPBrunelliECasaburiICatalanoSBrunoRSisciDAndoS2010Akt2 inhibition enables the forkhead transcription factor FoxO3a to have a repressive role in estrogen receptor α transcriptional activity in breast cancer cells. Molecular and Cellular Biology30857870. (doi:10.1128/MCB.00824-09).

MoriMVignaroliGCauYDinicJHillRRossiMColecchiaDPesicMLinkWChiarielloM2014Discovery of 14-3-3 protein–protein interaction inhibitors that sensitize multidrug-resistant cancer cells to doxorubicin and the Akt inhibitor GSK690693. ChemMedChem9973983. (doi:10.1002/cmdc.201400044).

NowakKKillmerKGessnerCLutzW2007E2F-1 regulates expression of FOXO1 and FOXO3a. Biochimica et Biophysica Acta1769244252. (doi:10.1016/j.bbaexp.2007.04.001).

O'HurleyGDalyEO'GradyACumminsRQuinnCFlanaganLPierceAFanYLynnMARaffertyM2014Investigation of molecular alterations of AKT-3 in triple-negative breast cancer. Histopathology64660670. (doi:10.1111/his.12313).

OsborneCKSchiffR2011Mechanisms of endocrine resistance in breast cancer. Annual Review of Medicine62233247. (doi:10.1146/annurev-med-070909-182917).

PaikJHKolliparaRChuGJiHXiaoYDingZMiaoLTothovaZHornerJWCarrascoDR2007FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell128309323. (doi:10.1016/j.cell.2006.12.029).

ParkEGongEYRomanelliMGLeeK2012Suppression of estrogen receptor-α transactivation by thyroid transcription factor-2 in breast cancer cells. Biochemical and Biophysical Research Communications421532537. (doi:10.1016/j.bbrc.2012.04.039).

ParryPWeiYEvansG1994Cloning and characterization of the t(X;11) breakpoint from a leukemic cell line identify a new member of the forkhead gene family. Genes Chromosomes & Cancer117984. (doi:10.1002/gcc.2870110203).

PearceLRKomanderDAlessiDR2010The nuts and bolts of AGC protein kinases. Nature Reviews. Molecular Cell Biology11922. (doi:10.1038/nrm2822).

PerouCM2011Molecular stratification of triple-negative breast cancers. Oncologist16 (Suppl 1) 6170. (doi:10.1634/theoncologist.2011-S1-61).

PerouCMSorlieTEisenMBvan de RijnMJeffreySSReesCAPollackJRRossDTJohnsenHAkslenLA2000Molecular portraits of human breast tumours. Nature406747752. (doi:10.1038/35021093).

PiccartMHortobagyiGNCamponeMPritchardKILebrunFItoYNoguchiSPerezARugoHSDeleuI2014Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2†. Annals of Oncology2523572362. (doi:10.1093/annonc/mdu456).

PlasDRThompsonCB2003Akt activation promotes degradation of tuberin and FOXO3a via the proteasome. Journal of Biological Chemistry2781236112366. (doi:10.1074/jbc.M213069200).

PotenteMUrbichCSasakiKHofmannWKHeeschenCAicherAKolliparaRDePinhoRAZeiherAMDimmelerS2005Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization. Journal of Clinical Investigation11523822392. (doi:10.1172/JCI23126).

PritchardKIBurrisHAIIIItoYRugoHSDakhilSHortobagyiGNCamponeMCsosziTBaselgaJPuttawibulP2013Safety and efficacy of everolimus with exemestane vs. exemestane alone in elderly patients with HER2-negative, hormone receptor-positive breast cancer in BOLERO-2. Clinical Breast Cancer13421432.e8. (doi:10.1016/j.clbc.2013.08.011).

RenaGWoodsYLPrescottARPeggieMUntermanTGWilliamsMRCohenP2002Two novel phosphorylation sites on FKHR that are critical for its nuclear exclusion. EMBO Journal2122632271. (doi:10.1093/emboj/21.9.2263).

RodonJDienstmannRSerraVTaberneroJ2013Development of PI3K inhibitors: lessons learned from early clinical trials. Nature Reviews. Clinical Oncology10143153. (doi:10.1038/nrclinonc.2013.10).

RugoHSDosing and safety implications for oncologists when administering everolimus to patients with hormone receptor-positive breast cancerClinical Breast Cancer2015[in press]doi:10.1016/j.clbc.2015.09.004).

Schmitt-NeyMCamussiG2015The PAX3–FOXO1 fusion protein present in rhabdomyosarcoma interferes with normal FOXO activity and the TGF-β pathway. PLoS ONE10e0121474. (doi:10.1371/journal.pone.0121474).

SchuurERLoktevAVSharmaMSunZRothRAWeigelRJ2001Ligand-dependent interaction of estrogen receptor-α with members of the forkhead transcription factor family. Journal of Biological Chemistry2763355433560. (doi:10.1074/jbc.M105555200).

Seton-RogersS2015Breast cancer: untangling the role of progesterone receptors. Nature Reviews. Cancer15456. (doi:10.1038/nrc3991).

Shajahan-HaqANCookKLSchwartz-RobertsJLEltayebAEDemasDMWarriAMFaceyCOHilakivi-ClarkeLAClarkeR2014MYC regulates the unfolded protein response and glucose and glutamine uptake in endocrine resistant breast cancer. Molecular Cell13239. (doi:10.1186/1476-4598-13-239).

ShangYBrownM2002Molecular determinants for the tissue specificity of SERMs. Science29524652468. (doi:10.1126/science.1068537).

ShangYHuXDiRenzoJLazarMABrownM2000Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription. Cell103843852. (doi:10.1016/S0092-8674(00)00188-4).

SiegelRWardEBrawleyOJemalA2011Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA: A Cancer Journal for Clinicians61212236. (doi:10.3322/caac.20121).

SimonciniTHafezi-MoghadamABrazilDPLeyKChinWWLiaoJK2000Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature407538541. (doi:10.1038/35035131).

SisciDMarisPCesarioMGAnselmoWCoronitiRTrombinoGERomeoFFerraroALanzinoMAquilaS2013The estrogen receptor α is the key regulator of the bifunctional role of FoxO3a transcription factor in breast cancer motility and invasiveness. Cell Cycle1234053420. (doi:10.4161/cc.26421).

StalOPerez-TenorioGAkerbergLOlssonBNordenskjoldBSkoogLRutqvistLE2003Akt kinases in breast cancer and the results of adjuvant therapy. Breast Cancer Research5R37R44. (doi:10.1186/bcr569).

SublettJEJeonISShapiroDN1995The alveolar rhabdomyosarcoma PAX3/FKHR fusion protein is a transcriptional activator. Oncogene11545552.

SundaresanNRGuptaMKimGRajamohanSBIsbatanAGuptaMP2009Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. Journal of Clinical Investigation11927582771. (doi:10.1172/JCI39162).

ThorpeLMYuzugulluHZhaoJJ2015PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nature Reviews. Cancer15724. (doi:10.1038/nrc3860).

TokunagaEKimuraYOkiEUedaNFutatsugiMMashinoKYamamotoMIkebeMKakejiYBabaH2006Akt is frequently activated in HER2/neu-positive breast cancers and associated with poor prognosis among hormone-treated patients. International Journal of Cancer118284289. (doi:10.1002/ijc.21358).

TokunagaEHisamatsuYTanakaKYamashitaNSaekiHOkiEKitaoHMaeharaY2014Molecular mechanisms regulating the hormone sensitivity of breast cancer. Cancer Science10513771383. (doi:10.1111/cas.12521).

TurnerNPearsonASharpeRLambrosMGeyerFLopez-GarciaMANatrajanRMarchioCIornsEMackayA2010FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Research7020852094. (doi:10.1158/0008-5472.CAN-09-3746).

TzaharEWatermanHChenXLevkowitzGKarunagaranDLaviSRatzkinBJYardenY1996A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Molecular and Cellular Biology1652765287. (doi:10.1128/MCB.16.10.5276).

WangCXKoayDCEdwardsALuZMorGOcalITDigiovannaMP2005In vitro and in vivo effects of combination of trastuzumab (Herceptin) and tamoxifen in breast cancer. Breast Cancer Research and Treatment92251263. (doi:10.1007/s10549-005-3375-z).

WangFMarshallCBYamamotoKLiGYPlevinMJYouHMakTWIkuraM2008Biochemical and structural characterization of an intramolecular interaction in FOXO3a and its binding with p53. Journal of Molecular Biology384590603. (doi:10.1016/j.jmb.2008.09.025).

WangFMarshallCBLiGYYamamotoKMakTWIkuraM2009Synergistic interplay between promoter recognition and CBP/p300 coactivator recruitment by FOXO3a. ACS Chemical Biology410171027. (doi:10.1021/cb900190u).

WangFMarshallCBYamamotoKLiGYGasmi-SeabrookGMOkadaHMakTWIkuraM2012aStructures of KIX domain of CBP in complex with two FOXO3a transactivation domains reveal promiscuity and plasticity in coactivator recruitment. PNAS10960786083. (doi:10.1073/pnas.1119073109).

WangFChanCHChenKGuanXLinHKTongQ2012bDeacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation. Oncogene3115461557. (doi:10.1038/onc.2011.347).

WangYQCaoQWangFHuangLYSangTTLiuFChenSY2015SIRT1 protects against oxidative stress-induced endothelial progenitor cells apoptosis by inhibiting FOXO3a via FOXO3a ubiquitination and degradation. Journal of Cellular Physiology23020982107. (doi:10.1002/jcp.24938).

WebbAEBrunetA2014FOXO transcription factors: key regulators of cellular quality control. Trends in Biochemical Sciences39159169. (doi:10.1016/j.tibs.2014.02.003).

WeigelDJackleH1990The fork head domain: a novel DNA binding motif of eukaryotic transcription factors?Cell63455456. (doi:10.1016/0092-8674(90)90439-L).

WeigelDJurgensGKuttnerFSeifertEJackleH1989The homeotic gene fork head encodes a nuclear protein and is expressed in the terminal regions of the Drosophila embryo. Cell57645658. (doi:10.1016/0092-8674(89)90133-5).

WijchersPJBurbachJPSmidtMP2006In control of biology: of mice, men and Foxes. Biochemical Journal397233246. (doi:10.1042/BJ20060387).

WondisfordARXiongLChangEMengSMeyersDJLiMColePAHeL2014Control of Foxo1 gene expression by co-activator P300. Journal of Biological Chemistry28943264333. (doi:10.1074/jbc.M113.540500).

WrightTMWardellSEJasperJSSticeJPSafiRNelsonERMcDonnellDP2014Delineation of a FOXA1/ERα/AGR2 regulatory loop that is dysregulated in endocrine therapy-resistant breast cancer. Molecular Cancer Research1218291839. (doi:10.1158/1541-7786.MCR-14-0195).

YangJYZongCSXiaWYamaguchiHDingQXieXLangJYLaiCCChangCJHuangWC2008ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nature Cell Biology10138148. (doi:10.1038/ncb1676).

YardleyDANoguchiSPritchardKIBurrisHAIIIBaselgaJGnantMHortobagyiGNCamponeMPistilliBPiccartM2013Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Advances in Therapy30870884. (doi:10.1007/s12325-013-0060-1).

YoriJLLozadaKLSeachristDDMosleyJDAbdul-KarimFWBoothCNFlaskCAKeriRA2014Combined SFK/mTOR inhibition prevents rapamycin-induced feedback activation of AKT and elicits efficient tumor regression. Cancer Research7447624771. (doi:10.1158/0008-5472.CAN-13-3627).

YuanZBeckerEBMerloPYamadaTDiBaccoSKonishiYSchaeferEMBonniA2008Activation of FOXO1 by Cdk1 in cycling cells and postmitotic neurons. Science31916651668. (doi:10.1126/science.1152337).

ZhangFKellyWL2012In vivo production of thiopeptide variants. Methods in Enzymology516324. (doi:10.1016/B978-0-12-394291-3.00022-8).

ZhangYGanBLiuDPaikJH2011FoxO family members in cancer. Cancer Biology & Therapy12253259. (doi:10.4161/cbt.12.4.15954).

ZhaoHHHerreraRECoronado-HeinsohnEYangMCLudes-MeyersJHSeybold-TilsonKJNawazZYeeDBarrFGDiabSG2001Forkhead homologue in rhabdomyosarcoma functions as a bifunctional nuclear receptor-interacting protein with both coactivator and corepressor functions. Journal of Biological Chemistry2762790727912. (doi:10.1074/jbc.M104278200).

ZhouXTanMStone HawthorneVKlosKSLanKHYangYYangWSmithTLShiDYuD2004Activation of the Akt/mammalian target of rapamycin/4E-BP1 pathway by ErbB2 overexpression predicts tumor progression in breast cancers. Clinical Cancer Research1067796788. (doi:10.1158/1078-0432.CCR-04-0112).

ZieglerSF2006FOXP3: of mice and men. Annual Review of Immunology24209226. (doi:10.1146/annurev.immunol.24.021605.090547).

ZouYTsaiWBChengCJHsuCChungYMLiPCLinSHHuMC2008Forkhead box transcription factor FOXO3a suppresses estrogen-dependent breast cancer cell proliferation and tumorigenesis. Breast Cancer Research10R21. (doi:10.1186/bcr1872).

Cited By

PubMed

Google Scholar