The role of steroid hormones in breast cancer stem cells

in Endocrine-Related Cancer

Breast cancer stem cells (BCSCs) are potent tumor-initiating cells in breast cancer, the most common cancer among women. BCSCs have been suggested to play a key role in tumor initiation which can lead to disease progression and formation of metastases. Moreover, BCSCs are thought to be the unit of selection for therapy-resistant clones since they survive conventional treatments, such as chemotherapy, irradiation, and hormonal therapy. The importance of the role of hormones for both normal mammary gland and breast cancer development is well established, but it was not until recently that the effects of hormones on BCSCs have been investigated. This review will discuss recent studies highlighting how ovarian steroid hormones estrogen and progesterone, as well as therapies against them, can regulate BCSC activity.

Abstract

Breast cancer stem cells (BCSCs) are potent tumor-initiating cells in breast cancer, the most common cancer among women. BCSCs have been suggested to play a key role in tumor initiation which can lead to disease progression and formation of metastases. Moreover, BCSCs are thought to be the unit of selection for therapy-resistant clones since they survive conventional treatments, such as chemotherapy, irradiation, and hormonal therapy. The importance of the role of hormones for both normal mammary gland and breast cancer development is well established, but it was not until recently that the effects of hormones on BCSCs have been investigated. This review will discuss recent studies highlighting how ovarian steroid hormones estrogen and progesterone, as well as therapies against them, can regulate BCSC activity.

Breast cancer stem cells

The cancer stem cell (CSC) theory proposes a hierarchical organization of the cells within a tumor, where only a small subset of cells, the CSCs, is believed to drive and sustain tumor growth. CSCs are defined as self-renewing tumor-initiating cells (TICs), which would implicate them in tumor relapse and resistance to therapy, making them an important therapeutic target (Reya et al. 2001).

The first report establishing the presence of breast CSCs (BCSCs) discovered that CD44+CD24/lowESA+lineage (named CD44+CD24 henceforth) cells, isolated from human breast tumors by FACS, were enriched for tumor-initiating capacity in immuno-compromised mice (Al-Hajj et al. 2003). CD44+CD24 cells can be serially passaged and form tumors containing both tumorigenic cells (CD44+CD24) and non-tumorigenic cells. Breast cancers with high levels of CD44 and low levels of CD24 have been associated with the triple negative phenotype (i.e. lacking estrogen receptor (ER), progesterone receptor (PR), and HER2 expression) and inferior overall survival (Liu et al. 2007, Honeth et al. 2008).

Besides isolation of CD44+CD24 cells, other strategies have been used to identify populations enriched for BCSC activity. Mammosphere formation, high aldehyde dehydrogenase (ALDH) activity, capacity to retain PKH26 dye or ability to efflux lipophilic dyes (side population (SP)), are all examples of properties that have been used to isolate these TICs. The mammosphere colony assay relies on the ability of BCSCs to survive in non-adherent serum-free culture conditions and form individual spherical colonies, called mammospheres (Dontu et al. 2003, Ponti et al. 2005, Farnie et al. 2007). On the other hand, the activity of ALDH1, which oxidizes intracellular aldehydes, is detected by an enzymatic assay (ALDEFLUOR) and flow cytometric analysis (Ginestier et al. 2007). The proportion of cells expressing ALDH1 in breast tumors has been shown to correlate with poor clinical outcome (Ginestier et al. 2007, Charafe-Jauffret et al. 2010). The PKH26 dye, which labels quiescent cells, has also been used to identify BCSCs in primary breast tumors by FACS sorting cells expressing CD49f, DLL1, and DNER (Pece et al. 2010). Hoechst dye exclusion activity has also been described as a method to identify a cellular fraction termed the SP that contains tumorigenic stem/progenitor cells (Patrawala et al. 2005). Finally, an autofluorescent epithelial CSC phenotype has recently been reported, however it still remains to be proven whether it can be used to identify BCSCs (Miranda-Lorenzo et al. 2014).

There remains a lack of consensus as to the most robust method for the purification of BCSCs. The establishment of bona fide BCSC markers is hindered by breast cancer intra-tumor and inter-tumor heterogeneity of its cell populations. Nevertheless, the two most widely used cell populations to enrich for BCSCs are CD44+CD24 and ALDH+.

A recent study reported that these two cell populations identify BCSCs in different states with gene expression profiles resembling cells with either mesenchymal (CD44+CD24 cells) or epithelial characteristics (ALDH+ cells) (Liu et al. 2014). Moreover, this study identified a small overlapping population of cells that is both CD44+CD24 and ALDH+, and suggested that BCSCs display cellular plasticity by dynamically switching between the mesenchymal and epithelial states. This epithelial–mesenchymal transition or vice-versa (mesenchymal–epithelial transition) is believed to be determined by the tumor microenvironment, with factors like hypoxia or transforming growth factor beta playing a key role in this process (Thiery 2002, Yang et al. 2008). It is feasible that other signaling factors that have been reported to modulate BCSC activity, such as hormones, may also influence this dynamic state.

In this review, we will discuss what is known about the regulation of BCSC function by the steroid hormones estrogen and progesterone and their antagonists.

Estrogen and BCSCs

Estrogen is essential for the development of normal breast epithelium by promoting epithelial cell proliferation and ductal morphogenesis but also plays an important role in the growth of most breast cancers through their expression of ER (Bocchinfuso & Korach 1997, Colditz 1998). Epidemiological evidence suggests that breast cancer risk is positively associated with post-menopausal levels of estrogen (Clemons & Goss 2001). Estrogen effects are mainly mediated through binding to two nuclear ligand-activated transcription factors, the ERs ERα and ERβ, which then bind estrogen-responsive elements in the DNA to regulate the transcription of target genes (Yager & Davidson 2006). In the normal breast, ERα is found in luminal epithelial cells, but not in the stroma, whereas ERβ has been shown to be expressed in both luminal and myoepithelial cells, as well as stromal cells, such as fibroblasts and endothelial cells (Petersen et al. 1987, Speirs et al. 2002). ERα, which has a higher affinity to the physiological form of estrogen, 17β-estradiol, than ERβ, has been shown to be the major mediator of estrogen action (Bocchinfuso & Korach 1997, Kuiper et al. 1998). ERα (named ER henceforth) is a key regulator of breast cancer and its expression status is currently used together with other receptors in the classification of breast cancer subtypes. ER+ tumors are strongly associated with the luminal subtype and are generally characterized by expression of luminal differentiation markers (Perou et al. 2000).

Although the importance of estrogen in breast cancer is well established, the effects of estrogen on BCSCs are not fully understood and are still a matter of debate (Simões & Vivanco 2011). Estrogen may exert influence on stem cells via paracrine mechanisms because CD44+CD24 and ALDH+ CSCs have been shown to lack expression of ER or express it at very low levels (Morimoto et al. 2009, Harrison et al. 2013, Simões et al. 2015). Similar to what happens in the normal mammary gland, it has been suggested that estrogen can promote CSC activity of ER BCSCs by inducing the secretion of paracrine growth factors from ER+ cells. Fibroblast growth factor (FGF)/Tbx3 signalling, as well as epidermal growth factor (EGF) and Notch receptor signalling pathways, have been reported to control this paracrine mechanism and induce the expansion of CD44+CD24 CSCs (Fillmore et al. 2010, Harrison et al. 2013). In contrast to these findings, estrogen was shown to reduce the self-renewal capacity of MCF7 BCSCs by promoting differentiation through down-regulation of embryonic stem cell genes NANOG, OCT4, and SOX2 (Simões et al. 2011). These contradictory results may be due to differences in the methods used in these studies. Fillmore et al. and Harrison et al. exposed breast cancer cells grown in monolayer adherent culture (not enriched for CSCs) to estrogen whereas Simões et al. challenged BCSCs with estrogen by growing cells in non-adherent mammosphere culture conditions. Therefore, opposing effects of estrogen on CSC activity seem to be determined by the context in which the cells are cultured and by the analysis of different breast cancer cell populations.

The role of estrogen in clinical breast carcinogenesis is also contradictory. Whereas high levels of endogenous estrogens increase the risk of postmenopausal breast cancer, randomised trials of exogenous estrogen alone (hormone replacement therapy) show it to reduce the incidence and mortality of breast cancer (Women's Health Initiative) (LaCroix et al. 2011). This finding is similar to animal models where short-term treatment with pregnancy levels of estrogen can prevent the formation of mammary tumors (Rajkumar et al. 2001). This anti-cancer effect of estrogen has been suggested to explain the breast cancer preventative potential of early full-term pregnancy to lifetime breast cancer risk, although this cannot be attributed solely to estrogen levels given the complexity of pregnancy associated endocrine perturbation (Medina 2004). Hypothetically, the protective effect of estrogen may be due to breast stem cell differentiation during pregnancy and lactation, which would reduce the number of stem cells that could be precursors of cancer (Russo et al. 2005, Simões & Vivanco 2011). To add further complexity to the role of estrogen in breast cancer, higher doses have been used for many years to treat advanced disease, with response rates similar to those seen with the anti-estrogens (Ellis et al. 2009, Lewis-Wambi & Jordan 2009). Without doubt, more studies are needed to explore the complexities of estrogen signalling, stem cells and breast cancer risk and progression.

Endocrine resistance: biomarkers, up-regulated pathways, and BCSCs

Around 75% of breast cancers express ER and are treated with anti-estrogen adjuvant therapies to suppress ER mediated estrogen signaling and, therefore, inhibit proliferation of ER+ breast cancer cells (Ali & Coombes 2002). There are three main classes of anti-estrogen drugs that target and modulate ER activity: selective ER modulators (SERMs), aromatase inhibitors (AIs), and selective ER down-regulators (SERDs). The most common and successful SERM is tamoxifen, which prevents the effects of estrogen by competing for the ER ligand-binding site (Shiau et al. 1998). AIs block the function of aromatase, the enzyme that catalyses the last step of estrogen biosynthesis (Mokbel 2002). Tamoxifen and AIs are the endocrine therapies of choice in the adjuvant treatment of premenopausal and postmenopausal women respectively (Beelen et al. 2012). These and other anti-estrogens, such as the SERD fulvestrant, which binds ER and targets it for degradation through ubiquitination, are used sequentially in advanced breast cancer (Howell et al. 2004). Endocrine sensitivity can partly be predicted by serial analysis of the proliferation marker Ki67 expression in pre-surgical ‘window’ studies or longer term neoadjuvant studies of several months of treatment (Dowsett et al. 2011). More recently, a four-gene signature including genes related to immune signalling (IL6ST), apoptosis (NGFRAP1), and proliferation (ASPM and MCM4) was reported to predict the clinical response of patients treated with AIs (Turnbull et al. 2015). However, despite the undoubted success of tamoxifen (or similar endocrine) treatment, at least half of patients with micrometastatic disease will relapse despite therapy, often many years after initial surgery and endocrine therapy is completed (Early Breast Cancer Trialists' Collaborative Group et al. 2011).

Such endocrine resistance compromises this otherwise effective treatment and thus the potential cure of ER+ breast cancers. Therefore, defining the mechanisms of endocrine resistance is a major research focus. Activation of classical signalling pathways, including the ones induced by HER2 and EGF receptor (EGFR), MAPK, and PI3K/AKT have been implicated in hormone resistance (Musgrove & Sutherland 2009). However, the only approved targeted therapies to improve outcomes of endocrine-resistant ER+ HER2 breast cancers are the mTOR inhibitor everolimus and the CDK4/6 inhibitor palbociclib combined with an AI or fulvestrant (Baselga et al. 2012, Finn et al. 2015, Turner et al. 2015). Therefore, a better understanding of the molecular changes associated with endocrine resistant growth is urgently needed to find treatments that can inhibit or delay the emergence of resistance.

BCSCs, which can survive for long periods in a dormant state, may be associated with tumor recurrence and metastases. These cells have been shown to be more resistant to chemo- and radio-therapies than non-CSCs (Phillips et al. 2006, Li et al. 2008). In endocrine therapy, accumulating evidence suggests that there is an increase in BCSCs in ER+ breast cancer following anti-estrogen treatment. Two studies have reported enrichment for cells with both BCSC gene and marker expression in breast tumor tissue following short term AI (letrozole) or tamoxifen treatment (Creighton et al. 2010, Kabos et al. 2011). Additionally, other studies demonstrated similar effects in ER+ breast cancer cell lines. For example, tamoxifen treatment increased both the number of mammospheres and the expression of NANOG, OCT4, and SOX2 in MCF7 breast cancer cells (Simões et al. 2011, Piva et al. 2014). MCF7 mammospheres were also shown to be resistant to high doses of tamoxifen (Cariati et al. 2008). Moreover, tamoxifen, fulvestrant, or estrogen deprivation increased the percentage of cells expressing cytokeratin 5 (CK5), a marker of human breast stem/progenitor cells also found in BCSCs, in T47D breast cancer cells (Creighton et al. 2010, Kabos et al. 2011). These data confirm that, while endocrine therapies target the differentiated proliferative breast cancer cells, they cannot effectively target the BCSCs.

Stem cell activity in ER+ tumors is mainly due to a minority population of ER cells, which cannot be directly targeted by anti-estrogens and therefore might be responsible for resistance and recurrence (Harrison et al. 2013, Simões et al. 2015). Indeed, circulating tumor cells of ER+ primary tumors are in general found to be ER (Fehm et al. 2009). In the clinic, ER negativity is associated with poor prognosis, precluding a response to all categories of anti-estrogen treatment and associating with a more aggressive and proliferative phenotype. Interestingly, expression of putative regulators of ER BCSC activity like EGFR (Harrison et al. 2013), HER2 (Ithimakin et al. 2013), and FGF receptor (Fillmore et al. 2010), potentially resulting from selection of cells with a more stem-like phenotype have been associated with acquisition of endocrine resistance (McClelland et al. 2001, Hutcheson et al. 2003, Knowlden et al. 2003). Recently, the ER splice variant ERα36, which lacks both transactivation domains AF1 and AF2, was associated with BCSC regulation and endocrine resistance (Wang et al. 2005, Deng et al. 2014). Specifically, Deng et al. showed ERα36 to be essential for CD44+CD24 BCSC enrichment induced by tamoxifen or fulvestrant. ERα36 is reported to be located in the cellular membrane and cytoplasm, and to rapidly activate MAPK/ERK signalling in the presence of estrogen. However, future studies are needed to better understand the importance of ERα36 isoform in BCSCs maintenance (Wang et al. 2006).

The potential involvement of BCSCs in endocrine resistance makes it imperative to understand the cellular signalling pathways that could be targeted to eradicate BCSCs and provide long-term disease-free survival. It has been established that these cells are dependent upon developmental signalling pathways, which may provide suitable targets for therapeutic intervention (reviewed in Visvader & Lindeman (2012)). For example, activation of Wnt signalling due to high expression levels of stem cell marker SOX2 has been reported as an important tamoxifen-resistance mechanism (Piva et al. 2014). Another strong candidate for endocrine-resistant CSC regulation is the Notch pathway, which comprises four different transmembrane receptors (Notch1–4), five known surface-bound ligands (Delta-like 1, Delta-like 3, Delta-like 4, Jagged 1, and Jagged 2) and multiple transcriptional targets, including the Hes and Hey family of genes (Brennan & Brown 2003). It was previously shown that aberrant Notch activation is found in human breast cancers and correlates with recurrence within 5 years in ductal carcinoma in situ (DCIS) lesions (Stylianou et al. 2006, Farnie et al. 2007). Moreover, it was established that inhibition of the Notch signalling pathway reduces BCSC activity, and that the Notch4 receptor has a key role in controlling BCSCs (Harrison et al. 2010). Recently, our group demonstrated that treating ER+ breast cancer cells with endocrine therapies leads to increased Jag1–Notch4 signalling and that combining endocrine therapies with a Notch pathway inhibitor can prevent BCSC enrichment induced by endocrine therapies (Simões et al. 2015). Our results suggest that inhibition of Notch signalling can help overcoming endocrine therapy resistance and might prevent recurrence in ER+ breast cancer. Importantly, we also showed that both Notch4 activation and high expression of BCSC marker ALDH1 in patient primary tumors are predictors of resistance to endocrine treatments (Simões et al. 2015).

In summary, we speculate that BCSCs evade endocrine therapies, lie dormant and eventually re-initiate tumors in metastatic sites after treatment. Thus, BCSC-targeted therapies in combination with established anti-estrogens are likely to improve outcomes for breast cancer patients.

Progesterone and BCSCs

Progesterone has been shown to be vital for both pubertal side branching and lobular alveolar development of the mammary gland during pregnancy (Lydon et al. 1995, Brisken 2013). Importantly, in premenopausal women breast epithelial cell proliferation is highest in the progesterone dominant luteal phase of the menstrual cycle (Potten et al. 1988, Navarrete et al. 2005). Studies in mice have shown that mammary gland development results from progesterone-induced expansion of the mammary stem cell pool and have also shown that PR is important for carcinogen-induced mammary tumor formation (Lydon et al. 1999, Asselin-Labat et al. 2010, Joshi et al. 2010). In normal human breast cells, progesterone stimulation in matrix-embedded culture increased bipotent progenitor cell numbers (Graham et al. 2009).

The progesterone signal is mediated by the PR, which comprises two isoforms (PRA and PRB) that are only differentiated by a third activation function domain on the 5′ end of PRB (Kastner et al. 1990). The two isoforms are generally co-expressed at similar levels in the normal breast but the ratio can be altered in human breast tumors, resulting in a predominance of one particular isoform, usually PRA, over its counterpart (Graham et al. 2005, 2009). Isoform-specific mouse mutants reveal that PRB is the functionally important form in mammary gland morphogenesis, whereas PRA is important for ovarian function (Mulac-Jericevic et al. 2000, 2003). These isoforms display only partially overlapping transcriptional signatures with PRB modulating expression of significantly more genes than PRA (Richer et al. 2002). Relative loss of PRB is seen with the development of atypia or malignancy and in women with germline mutations in BRCA1 or BRCA2 (Mote et al. 2002). Interestingly, women with such mutations have double the serum progesterone levels compared to age matched WT controls although the significance of this finding is not known (Widschwendter et al. 2013).

In the normal mammary tissue, progesterone-induced gland expansion is mediated through paracrine proliferative signals, including receptor activator of nuclear factor-kappa B ligand (RANKL) and WNT4, secreted from PR+ sensor cells and acting on PR stem cells, expressing the RANK receptor and Wnt receptors, such as Frizzled (FZD) and LRP5/6 (Graham et al. 2009, Gonzalez-Suarez et al. 2010, Joshi et al. 2010). In multiple rodent models, deletion or inhibition of PR or the RANK/RANKL pathway results in significant reduction in mammary carcinogenesis (Lydon et al. 1999, Poole et al. 2006, Gonzalez-Suarez et al. 2010, Schramek et al. 2010). Recent evidence has established CXCR4 receptor and its ligand CXCL12 as potential key mediators of progesterone-induced stem/progenitor cell functions in normal mammary gland (Shiah et al. 2015). CXCL12 is localized on PR+ luminal cells whereas CXCR4 is induced by progesterone in both basal and luminal PR cells. Significantly, Shiah et al. showed that inhibition of CXCR4–CXCL12 signalling is able to arrest the progesterone-induced expansion of mammary stem/progenitor cells. Finally, it has been demonstrated recently that progesterone induces growth hormone (GH) secretion in human breast epithelial cells, which increases proliferation of GH receptor (GHR) positive stem/progenitor breast cells (Lombardi et al. 2014).

In an analogous manner progesterone has been shown to expand the population of BCSCs in breast cancer cell lines. In particular, progesterone was shown to increase the population of CK5+ and CD44hi or CD44+CD24 BCSCs in several ER+PR+ cell lines but particularly in T47D cells, which express high levels of PR even in the absence of estrogen (Axlund et al. 2013, Finlay-Schultz et al. 2014, Hilton et al. 2014). Importantly, in cell lines where PR expression is dependent on estrogen, cells need to be treated with estrogen and progesterone, while estrogen alone was not able to induce BCSCs.

The mechanisms behind the progesterone-induced expansion of BCSCs have not been fully elucidated. However, progesterone treatment of cell lines has been shown to repress miR-29 and miR-141, de-repressing KLF4 and STAT5A respectively (Cittelly et al. 2013, Finlay-Schultz et al. 2014). In both studies, this resulted in expansion of the CK5+/CD44+ CSC population and enhancement of colony formation and tumor initiating capacity. KLF4 is a transcription factor required for maintenance of both BCSCs (Yu et al. 2011) and pluripotency in embryonic stem cells (Zhang et al. 2010) whereas STAT5A is a transcription factor that regulates the mammary luminal progenitor population (Yamaji et al. 2009). BCL6, which appears to be critical in the maintenance of some leukaemic stem cells, was also reported to be essential for progesterone-induction of CK5+ cells (Hurtz et al. 2011, Sato et al. 2014). Interestingly, the progesterone-induced expression of BCL6 was inhibited by prolactin, further demonstrating the complex interplay between hormonal signalling axes in the regulation of BCSCs (Sato et al. 2014). It is also possible that PR+ cells communicate with PR BCSCs through similar paracrine pathways as in the normal mammary gland. Indeed, non-endogenous overexpression of RANK in human breast cell lines induces stemness by increasing the CD44+CD24 BCSC population, promoting tumour initiation and metastasis (Palafox et al. 2012). However, clinical trials of the RANKL inhibitor denosumab do not show any improvement in cancer control or survival despite their valuable role in reducing skeletal complications from bone metastases. In summary, this evidence suggests that progesterone is responsible for the expansion of both normal and breast cancer stem cells but that the precise mechanisms may be divergent. However, both the PR itself and some of the paracrine/downstream signals described are targetable and may hold promise as breast cancer therapies.

Anti-progesterone drugs and BCSCs

Women's Health Initiative study reports that combination of estrogen with progestin (synthetic progesterone derivative), but not estrogen alone was associated with greater breast cancer incidence and mortality (Chlebowski et al. 2010). The progesterone role in mammary tumorigenesis may be explained by the expansion of stem cell populations, which are likely to originate BCSCs and lead to the formation of ER+PR+ tumors (Narod 2011).

Despite much promise in the early 1990s, no anti-progestin is a recommended standard of care in anti-cancer treatment. However, there is a renewed interest in anti-progestin drugs indicated by several current clinical trials using mifepristone and onapristone in breast cancer and other solid tumors (see NCT01493310, NCT02014337, NCT02046421, NCT02049190, and NCT02052128 on US clinical trials database, https://clinicaltrials.gov/). Based on recent research, it is possible that these drugs target BCSCs in ER+PR+ tumors, although this remains hypothetical and merits further investigation.

Conclusions

The published data suggests that in breast cancer both estrogen and progesterone signalling have multifarious effects on CSC activity. Since BCSCs are reported to be low or negative for steroid hormone receptors, the effects are likely to be mainly indirect, transmitted through paracrine or juxtacrine cell–cell signalling pathways (Fig. 1). We do not exclude the possibility that there is some autocrine signalling downstream of hormones that may contribute to regulation of BCSCs. The effects of estrogen and progesterone have only been partially described in cancer tissues. For progesterone in particular there is more data from normal mammary epithelium than from cancer tissues.

Figure 1
Figure 1

Schematic representation of paracrine and juxtacrine signals involved in estrogen and progesterone regulation of BCSCs. Estrogen and progesterone bind estrogen receptor (ER) and progesterone receptor (PR) nuclear transcription factors, respectively, regulating expression of target genes. Estrogen sensor cells (non-BCSCs) increase transcription of epidermal growth factor (EGF), amphiregulin (AREG), transforming growth factor alpha (TGFα), and fibroblast growth factor (FGF), which will signal to the BCSCs through the EGFRs and FGFRs. Non-BCSCs can also signal to the BCSCs via Notch signalling. Progesterone sensor cells (non-BCSCs) also increase transcription of several important signalling factors. Progesterone regulation of BCSCs may occur via activation of RANK/RANKL, Wnt receptors/Wnt4, CXCR4/CXCL12, and GHR/GH paracrine signalling (dashed lines). Estrogen and progesterone-induced signals can be blocked by anti-estrogens (e.g. tamoxifen and fulvestrant) and anti-progesterone drugs (e.g. mifepristone and onapristone).

Citation: Endocrine-Related Cancer 22, 6; 10.1530/ERC-15-0350

For estrogen, there are reports that following in vitro treatment of serum-starved breast cancer cells, CSC activity is stimulated and that this requires regulation by EGF, FGF, or Notch1 receptors, suggesting indirect, paracrine or juxtacrine signalling between cells (Fig. 1). On the other hand, anti-estrogens, such as tamoxifen or fulvestrant, block direct effects of estrogens on cell growth, and the indirect signals to the ER BCSCs. Paradoxically however, tamoxifen has been demonstrated to increase BCSC activity in mammosphere colony culture (Simões et al. 2011, Piva et al. 2014), and more recently, the same has been confirmed for both tamoxifen and fulvestrant in vivo (Simões et al. 2015). The data suggest that while anti-estrogens are cytostatic for the ER+ cells, there is an increase in the proportion of ER BCSCs and their activity. This increase could be due to selective enrichment by treatment, by induction of a change in cellular phenotype from ER+ non-BCSC to ER BCSC, or possibly a combination of both of these effects. Whatever the reason, the mechanism for the increase induced by anti-estrogens is reported to be Jag1–Notch4 signalling between ER BCSCs (Simões et al. 2015), rather than the signals from the ER+ cell shown here (Fig. 1).

For progesterone, the data are clear it has a role in regulating the expansion of normal mammary stem and progenitor cells through several signalling pathways including CXCL12/CXCR4, GH/GHR, WNT4/FZD, and RANKL/RANK. In breast cancer, there are cell line data suggesting that progesterone may regulate BCSCs but the importance of the previous signalling networks is not established (Fig. 1). Since progesterone does not directly stimulate proliferation in most breast cancers, the role for anti-progesterone drugs in breast cancer may be to abrogate progesterone effects on BCSC activities, although this is yet to be proven.

In summary, the data accumulated thus far indicate that estrogen and progesterone have mostly indirect effects on BCSCs since they are mainly ER and PR cells. Results from both normal and malignant epithelial cell–cell interactions suggest that estrogen and progesterone elicit these effects through different paracrine/juxtacrine regulatory pathways. Finally, since there are several putative pathways downstream of each estrogen and progesterone, there will be interactions and redundancy between these, yielding a subtle complexity in the consequences for the BCSC.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review.

Funding

The authors' work is supported by funding from Breast Cancer Now.

Acknowledgements

The authors would like to apologize to those authors whose work was not cited due to space limitations.

References

  • Al-HajjMWichaMSBenito-HernandezAMorrisonSJClarkeMF2003Prospective identification of tumorigenic breast cancer cells. PNAS10039833988. (doi:10.1073/pnas.0530291100).

    • Search Google Scholar
    • Export Citation
  • AliSCoombesRC2002Endocrine-responsive breast cancer and strategies for combating resistance. Nature Reviews. Cancer2101112. (doi:10.1038/nrc721).

    • Search Google Scholar
    • Export Citation
  • Asselin-LabatMLVaillantFSheridanJMPalBWuDSimpsonERYasudaHSmythGKMartinTJLindemanGJ2010Control of mammary stem cell function by steroid hormone signalling. Nature465798802. (doi:10.1038/nature09027).

    • Search Google Scholar
    • Export Citation
  • AxlundSDYooBHRosenRBSchaackJKabosPLabarberaDVSartoriusCA2013Progesterone-inducible cytokeratin 5-positive cells in luminal breast cancer exhibit progenitor properties. Hormones & Cancer43649. (doi:10.1007/s12672-012-0127-5).

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

    • Search Google Scholar
    • Export Citation
  • BeelenKZwartWLinnSC2012Can predictive biomarkers in breast cancer guide adjuvant endocrine therapy?Nature Reviews. Clinical Oncology9529541. (doi:10.1038/nrclinonc.2012.121).

    • Search Google Scholar
    • Export Citation
  • BocchinfusoWPKorachKS1997Mammary gland development and tumorigenesis in estrogen receptor knockout mice. Journal of Mammary Gland Biology and Neoplasia2323334. (doi:10.1023/A:1026339111278).

    • Search Google Scholar
    • Export Citation
  • BrennanKBrownAM2003Is there a role for Notch signalling in human breast cancer?Breast Cancer Research56975. (doi:10.1186/bcr559).

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

    • Search Google Scholar
    • Export Citation
  • CariatiMNaderiABrownJPSmalleyMJPinderSECaldasCPurushothamAD2008Alpha-6 integrin is necessary for the tumourigenicity of a stem cell-like subpopulation within the MCF7 breast cancer cell line. International Journal of Cancer122298304. (doi:10.1002/ijc.23103).

    • Search Google Scholar
    • Export Citation
  • Charafe-JauffretEGinestierCIovinoFTarpinCDiebelMEsterniBHouvenaeghelGExtraJMBertucciFJacquemierJ2010Aldehyde dehydrogenase 1-positive cancer stem cells mediate metastasis and poor clinical outcome in inflammatory breast cancer. Clinical Cancer Research164555. (doi:10.1158/1078-0432.CCR-09-1630).

    • Search Google Scholar
    • Export Citation
  • ChlebowskiRTAndersonGLGassMLaneDSAragakiAKKullerLHMansonJEStefanickMLOckeneJSartoGE2010Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. Journal of the American Medical Association30416841692. (doi:10.1001/jama.2010.1500).

    • Search Google Scholar
    • Export Citation
  • CittellyDMFinlay-SchultzJHoweENSpoelstraNSAxlundSDHendricksPJacobsenBMSartoriusCARicherJK2013Progestin suppression of miR-29 potentiates dedifferentiation of breast cancer cells via KLF4. Oncogene3225552564. (doi:10.1038/onc.2012.275).

    • Search Google Scholar
    • Export Citation
  • ClemonsMGossP2001Estrogen and the risk of breast cancer. New England Journal of Medicine344276285. (doi:10.1056/NEJM200101253440407).

    • Search Google Scholar
    • Export Citation
  • ColditzGA1998Relationship between estrogen levels, use of hormone replacement therapy, and breast cancer. Journal of the National Cancer Institute90814823. (doi:10.1093/jnci/90.11.814).

    • Search Google Scholar
    • Export Citation
  • CreightonCJChangJCRosenJM2010Epithelial–mesenchymal transition (EMT) in tumor-initiating cells and its clinical implications in breast cancer. Journal of Mammary Gland Biology and Neoplasia15253260. (doi:10.1007/s10911-010-9173-1).

    • Search Google Scholar
    • Export Citation
  • DengHZhangX-TWangM-LZhengH-YLiuL-JWangZ-Y2014ER-α36-mediated rapid estrogen signaling positively regulates ER-positive breast cancer stem/progenitor cells. PLoS ONE9e88034. (doi:10.1371/journal.pone.0088034).

    • Search Google Scholar
    • Export Citation
  • DontuGAbdallahWMFoleyJMJacksonKWClarkeMFKawamuraMJWichaMS2003In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes and Development1712531270. (doi:10.1101/gad.1061803).

    • Search Google Scholar
    • Export Citation
  • DowsettMNielsenTOA'HernRBartlettJCoombesRCCuzickJEllisMHenryNLHughJCLivelyT2011Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. Journal of the National Cancer Institute10316561664. (doi:10.1093/jnci/djr393).

    • Search Google Scholar
    • Export Citation
  • Early Breast Cancer Trialists' Collaborative GroupDaviesCGodwinJGrayRClarkeMCutterDDarbySMcGalePPanHCTaylorC2011Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet378771784. (doi:10.1016/S0140-6736(11)60993-8).

    • Search Google Scholar
    • Export Citation
  • EllisMJGaoFDehdashtiFJeffeDBMarcomPKCareyLADicklerMNSilvermanPFlemingGFKommareddyA2009Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study. Journal of the American Medical Association302774780. (doi:10.1001/jama.2009.1204).

    • Search Google Scholar
    • Export Citation
  • FarnieGClarkeRBSpenceKPinnockNBrennanKAndersonNGBundredNJ2007Novel cell culture technique for primary ductal carcinoma in situ: role of Notch and epidermal growth factor receptor signaling pathways. Journal of the National Cancer Institute99616627. (doi:10.1093/jnci/djk133).

    • Search Google Scholar
    • Export Citation
  • FehmTHoffmannOAktasBBeckerSSolomayerEFWallwienerDKimmigRKasimir-BauerS2009Detection and characterization of circulating tumor cells in blood of primary breast cancer patients by RT-PCR and comparison to status of bone marrow disseminated cells. Breast Cancer Research11R59. (doi:10.1186/bcr2349).

    • Search Google Scholar
    • Export Citation
  • FillmoreCMGuptaPBRudnickJACaballeroSKellerPJLanderESKuperwasserC2010Estrogen expands breast cancer stem-like cells through paracrine FGF/Tbx3 signaling. PNAS1072173721742. (doi:10.1073/pnas.1007863107).

    • Search Google Scholar
    • Export Citation
  • Finlay-SchultzJCittellyDMHendricksPPatelPKabosPJacobsenBMRicherJKSartoriusCA2014Progesterone downregulation of miR-141 contributes to expansion of stem-like breast cancer cells through maintenance of progesterone receptor and Stat5a. Oncogene3436763687. (doi:10.1038/onc.2014.298).

    • Search Google Scholar
    • Export Citation
  • FinnRSCrownJPLangIBoerKBondarenkoIMKulykSOEttlJPatelRPinterTSchmidtM2015The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet. Oncology162535. (doi:10.1016/S1470-2045(14)71159-3).

    • Search Google Scholar
    • Export Citation
  • GinestierCHurMHCharafe-JauffretEMonvilleFDutcherJBrownMJacquemierJViensPKleerCGLiuS2007ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell1555567. (doi:10.1016/j.stem.2007.08.014).

    • Search Google Scholar
    • Export Citation
  • Gonzalez-SuarezEJacobAPJonesJMillerRRoudier-MeyerMPErwertRPinkasJBranstetterDDougallWC2010RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature468103107. (doi:10.1038/nature09495).

    • Search Google Scholar
    • Export Citation
  • GrahamJDYagerMLHillHDBythKO'NeillGMClarkeCL2005Altered progesterone receptor isoform expression remodels progestin responsiveness of breast cancer cells. Molecular Endocrinology1927132735. (doi:10.1210/me.2005-0126).

    • Search Google Scholar
    • Export Citation
  • GrahamJDMotePASalagameUvan DijkJHBalleineRLHuschtschaLIReddelRRClarkeCL2009DNA replication licensing and progenitor numbers are increased by progesterone in normal human breast. Endocrinology15033183326. (doi:10.1210/en.2008-1630).

    • Search Google Scholar
    • Export Citation
  • HarrisonHFarnieGHowellSJRockREStylianouSBrennanKRBundredNJClarkeRB2010Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Research70709718. (doi:10.1158/0008-5472.CAN-09-1681).

    • Search Google Scholar
    • Export Citation
  • HarrisonHSimõesBMRogersonLHowellSJLandbergGClarkeRB2013Oestrogen increases the activity of oestrogen receptor negative breast cancer stem cells through paracrine EGFR and Notch signalling. Breast Cancer Research15R21. (doi:10.1186/bcr3396).

    • Search Google Scholar
    • Export Citation
  • HiltonHNSantucciNSilvestriAKantimmSHuschtschaLIGrahamJDClarkeCL2014Progesterone stimulates progenitor cells in normal human breast and breast cancer cells. Breast Cancer Research and Treatment143423433. (doi:10.1007/s10549-013-2817-2).

    • Search Google Scholar
    • Export Citation
  • HonethGBendahlPORingnerMSaalLHGruvberger-SaalSKLovgrenKGrabauDFernoMBorgAHegardtC2008The CD44+/CD24 phenotype is enriched in basal-like breast tumors. Breast Cancer Research10R53. (doi:10.1186/bcr2108).

    • Search Google Scholar
    • Export Citation
  • HowellARobertsonJFAbramPLichinitserMRElledgeRBajettaEWatanabeTMorrisCWebsterADimeryI2004Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: a multinational, double-blind, randomized trial. Journal of Clinical Oncology2216051613. (doi:10.1200/JCO.2004.02.112).

    • Search Google Scholar
    • Export Citation
  • HurtzCHatziKCerchiettiLBraigMParkEKimYMHerzogSRamezani-RadPJumaaHMullerMC2011BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia. Journal of Experimental Medicine20821632174. (doi:10.1084/jem.20110304).

    • Search Google Scholar
    • Export Citation
  • HutchesonIRKnowldenJMMaddenTABarrowDGeeJMWakelingAENicholsonRI2003Oestrogen receptor-mediated modulation of the EGFR/MAPK pathway in tamoxifen-resistant MCF-7 cells. Breast Cancer Research and Treatment818193. (doi:10.1023/A:1025484908380).

    • Search Google Scholar
    • Export Citation
  • IthimakinSDayKCMalikFZenQDawseySJBersano-BegeyTFQuraishiAAIgnatoskiKWDaignaultSDavisA2013HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification: implications for efficacy of adjuvant trastuzumab. Cancer Research7316351646. (doi:10.1158/0008-5472.CAN-12-3349).

    • Search Google Scholar
    • Export Citation
  • JoshiPAJacksonHWBeristainAGDi GrappaMAMotePAClarkeCLStinglJWaterhousePDKhokhaR2010Progesterone induces adult mammary stem cell expansion. Nature465803807. (doi:10.1038/nature09091).

    • Search Google Scholar
    • Export Citation
  • KabosPHaughianJMWangXDyeWWFinlaysonCEliasAHorwitzKBSartoriusCA2011Cytokeratin 5 positive cells represent a steroid receptor negative and therapy resistant subpopulation in luminal breast cancers. Breast Cancer Research and Treatment1284555. (doi:10.1007/s10549-010-1078-6).

    • Search Google Scholar
    • Export Citation
  • KastnerPKrustATurcotteBStroppUToraLGronemeyerHChambonP1990Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. EMBO Journal916031614.

    • Search Google Scholar
    • Export Citation
  • KnowldenJMHutchesonIRJonesHEMaddenTGeeJMHarperMEBarrowDWakelingAENicholsonRI2003Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells. Endocrinology14410321044. (doi:10.1210/en.2002-220620).

    • Search Google Scholar
    • Export Citation
  • KuiperGGLemmenJGCarlssonBCortonJCSafeSHvan der SaagPTvan der BurgBGustafssonJA1998Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor β. Endocrinology13942524263.

    • Search Google Scholar
    • Export Citation
  • LaCroixAZChlebowskiRTMansonJEAragakiAKJohnsonKCMartinLMargolisKLStefanickMLBrzyskiRCurbJD2011Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. Journal of the American Medical Association30513051314. (doi:10.1001/jama.2011.382).

    • Search Google Scholar
    • Export Citation
  • Lewis-WambiJSJordanVC2009Estrogen regulation of apoptosis: how can one hormone stimulate and inhibit?Breast Cancer Research11206. (doi:10.1186/bcr2255).

    • Search Google Scholar
    • Export Citation
  • LiXLewisMTHuangJGutierrezCOsborneCKWuMFHilsenbeckSGPavlickAZhangXChamnessGC2008Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. Journal of the National Cancer Institute100672679. (doi:10.1093/jnci/djn123).

    • Search Google Scholar
    • Export Citation
  • LiuRWangXChenGYDalerbaPGurneyAHoeyTSherlockGLewickiJSheddenKClarkeMF2007The prognostic role of a gene signature from tumorigenic breast-cancer cells. New England Journal of Medicine356217226. (doi:10.1056/NEJMoa063994).

    • Search Google Scholar
    • Export Citation
  • LiuSCongYWangDSunYDengLLiuYMartin-TrevinoRShangLMcDermottSPLandisMD2014Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Reports27891. (doi:10.1016/j.stemcr.2013.11.009).

    • Search Google Scholar
    • Export Citation
  • LombardiSHonethGGinestierCShinomiyaIMarlowRBuchupalliBGazinskaPBrownJCatchpoleSLiuS2014Growth hormone is secreted by normal breast epithelium upon progesterone stimulation and increases proliferation of stem/progenitor cells. Stem Cell Reports2780793. (doi:10.1016/j.stemcr.2014.05.005).

    • Search Google Scholar
    • Export Citation
  • LydonJPDeMayoFJFunkCRManiSKHughesARMontgomeryCAJrShyamalaGConneelyOMO'MalleyBW1995Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes and Development922662278. (doi:10.1101/gad.9.18.2266).

    • Search Google Scholar
    • Export Citation
  • LydonJPGeGKittrellFSMedinaDO'MalleyBW1999Murine mammary gland carcinogenesis is critically dependent on progesterone receptor function. Cancer Research5942764284.

    • Search Google Scholar
    • Export Citation
  • McClellandRABarrowDMaddenTADutkowskiCMPammentJKnowldenJMGeeJMNicholsonRI2001Enhanced epidermal growth factor receptor signaling in MCF7 breast cancer cells after long-term culture in the presence of the pure antiestrogen ICI 182,780 (Faslodex). Endocrinology14227762788.

    • Search Google Scholar
    • Export Citation
  • MedinaD2004Breast cancer: the protective effect of pregnancy. Clinical Cancer Research10380S384S. (doi:10.1158/1078-0432.CCR-031211).

    • Search Google Scholar
    • Export Citation
  • Miranda-LorenzoIDoradoJLonardoEAlcalaSSerranoAGClausell-TormosJCioffiMMegiasDZagoracSBalicA2014Intracellular autofluorescence: a biomarker for epithelial cancer stem cells. Nature Methods1111611169. (doi:10.1038/nmeth.3112).

    • Search Google Scholar
    • Export Citation
  • MokbelK2002The evolving role of aromatase inhibitors in breast cancer. International Journal of Clinical Oncology7279283.

  • MorimotoKKimSJTaneiTShimazuKTanjiYTaguchiTTamakiYTeradaNNoguchiS2009Stem cell marker aldehyde dehydrogenase 1-positive breast cancers are characterized by negative estrogen receptor, positive human epidermal growth factor receptor type 2, and high Ki67 expression. Cancer Science10010621068. (doi:10.1111/j.1349-7006.2009.01151.x).

    • Search Google Scholar
    • Export Citation
  • MotePABartowSTranNClarkeCL2002Loss of co-ordinate expression of progesterone receptors A and B is an early event in breast carcinogenesis. Breast Cancer Research and Treatment72163172. (doi:10.1023/A:1014820500738).

    • Search Google Scholar
    • Export Citation
  • Mulac-JericevicBMullinaxRADeMayoFJLydonJPConneelyOM2000Subgroup of reproductive functions of progesterone mediated by progesterone receptor-B isoform. Science28917511754. (doi:10.1126/science.289.5485.1751).

    • Search Google Scholar
    • Export Citation
  • Mulac-JericevicBLydonJPDeMayoFJConneelyOM2003Defective mammary gland morphogenesis in mice lacking the progesterone receptor B isoform. PNAS10097449749. (doi:10.1073/pnas.1732707100).

    • Search Google Scholar
    • Export Citation
  • MusgroveEASutherlandRL2009Biological determinants of endocrine resistance in breast cancer. Nature Reviews. Cancer9631643. (doi:10.1038/nrc2713).

    • Search Google Scholar
    • Export Citation
  • NarodSA2011Hormone replacement therapy and the risk of breast cancer. Nature Reviews. Clinical Oncology8669676. (doi:10.1038/nrclinonc.2011.110).

    • Search Google Scholar
    • Export Citation
  • NavarreteMAMaierCMFalzoniRQuadrosLGLimaGRBaracatECNazarioAC2005Assessment of the proliferative, apoptotic and cellular renovation indices of the human mammary epithelium during the follicular and luteal phases of the menstrual cycle. Breast Cancer Research7R306R313. (doi:10.1186/bcr994).

    • Search Google Scholar
    • Export Citation
  • PalafoxMFerrerIPellegriniPVilaSHernandez-OrtegaSUrruticoecheaAClimentFSolerMTMunozPVinalsF2012RANK induces epithelial–mesenchymal transition and stemness in human mammary epithelial cells and promotes tumorigenesis and metastasis. Cancer Research7228792888. (doi:10.1158/0008-5472.CAN-12-0044).

    • Search Google Scholar
    • Export Citation
  • PatrawalaLCalhounTSchneider-BroussardRZhouJClaypoolKTangDG2005Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2 cancer cells are similarly tumorigenic. Cancer Research6562076219. (doi:10.1158/0008-5472.CAN-05-0592).

    • Search Google Scholar
    • Export Citation
  • PeceSTosoniDConfalonieriSMazzarolGVecchiMRonzoniSBernardLVialeGPelicciPGDi FiorePP2010Biological and molecular heterogeneity of breast cancers correlates with their cancer stem cell content. Cell1406273. (doi:10.1016/j.cell.2009.12.007).

    • Search Google Scholar
    • Export Citation
  • PerouCMSorlieTEisenMBvan de RijnMJeffreySSReesCAPollackJRRossDTJohnsenHAkslenLA2000Molecular portraits of human breast tumours. Nature406747752. (doi:10.1038/35021093).

    • Search Google Scholar
    • Export Citation
  • PetersenOWHoyerPEvan DeursB1987Frequency and distribution of estrogen receptor-positive cells in normal, nonlactating human breast tissue. Cancer Research4757485751.

    • Search Google Scholar
    • Export Citation
  • PhillipsTMMcBrideWHPajonkF2006The response of CD24(−/low)/CD44+ breast cancer-initiating cells to radiation. Journal of the National Cancer Institute9817771785. (doi:10.1093/jnci/djj495).

    • Search Google Scholar
    • Export Citation
  • PivaMDomeniciGIriondoORabanoMSimõesBMComaillsVBarredoILopez-RuizJAZabalzaIKyptaR2014Sox2 promotes tamoxifen resistance in breast cancer cells. EMBO Molecular Medicine66679. (doi:10.1002/emmm.201303411).

    • Search Google Scholar
    • Export Citation
  • PontiDCostaAZaffaroniNPratesiGPetrangoliniGCoradiniDPilottiSPierottiMADaidoneMG2005Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Research6555065511. (doi:10.1158/0008-5472.CAN-05-0626).

    • Search Google Scholar
    • Export Citation
  • PooleAJLiYKimYLinSCLeeWHLeeEY2006Prevention of Brca1-mediated mammary tumorigenesis in mice by a progesterone antagonist. Science31414671470. (doi:10.1126/science.1130471).

    • Search Google Scholar
    • Export Citation
  • PottenCSWatsonRJWilliamsGTTickleSRobertsSAHarrisMHowellA1988The effect of age and menstrual cycle upon proliferative activity of the normal human breast. British Journal of Cancer58163170. (doi:10.1038/bjc.1988.185).

    • Search Google Scholar
    • Export Citation
  • RajkumarLGuzmanRCYangJThordarsonGTalamantesFNandiS2001Short-term exposure to pregnancy levels of estrogen prevents mammary carcinogenesis. PNAS981175511759. (doi:10.1073/pnas.201393798).

    • Search Google Scholar
    • Export Citation
  • ReyaTMorrisonSJClarkeMFWeissmanIL2001Stem cells, cancer, and cancer stem cells. Nature414105111. (doi:10.1038/35102167).

  • RicherJKJacobsenBMManningNGAbelMGWolfDMHorwitzKB2002Differential gene regulation by the two progesterone receptor isoforms in human breast cancer cells. Journal of Biological Chemistry27752095218. (doi:10.1074/jbc.M110090200).

    • Search Google Scholar
    • Export Citation
  • RussoJMoralRBaloghGAMailoDRussoIH2005The protective role of pregnancy in breast cancer. Breast Cancer Research7131142. (doi:10.1186/bcr1029).

    • Search Google Scholar
    • Export Citation
  • SatoTTranTHPeckARGirondoMALiuCGoodmanCRNeilsonLMFreydinBChervonevaIHyslopT2014Prolactin suppresses a progestin-induced CK5-positive cell population in luminal breast cancer through inhibition of progestin-driven BCL6 expression. Oncogene3322152224. (doi:10.1038/onc.2013.172).

    • Search Google Scholar
    • Export Citation
  • SchramekDLeibbrandtASiglVKennerLPospisilikJALeeHJHanadaRJoshiPAAliprantisAGlimcherL2010Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature46898102. (doi:10.1038/nature09387).

    • Search Google Scholar
    • Export Citation
  • ShiahYJTharmapalanPCaseyAEJoshiPAMcKeeTDJacksonHWBeristainAGChan-Seng-YueMABaderGDLydonJP2015A progesterone–CXCR4 axis controls mammary progenitor cell fate in the adult gland. Stem Cell Reports4313322. (doi:10.1016/j.stemcr.2015.01.011).

    • Search Google Scholar
    • Export Citation
  • ShiauAKBarstadDLoriaPMChengLKushnerPJAgardDAGreeneGL1998The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell95927937. (doi:10.1016/S0092-8674(00)81717-1).

    • Search Google Scholar
    • Export Citation
  • SimõesBMVivancoMD2011Cancer stem cells in the human mammary gland and regulation of their differentiation by estrogen. Future Oncology79951006. (doi:10.2217/fon.11.80).

    • Search Google Scholar
    • Export Citation
  • SimõesBMPivaMIriondoOComaillsVLopez-RuizJAZabalzaIMiezaJAAcinasOVivancoMD2011Effects of estrogen on the proportion of stem cells in the breast. Breast Cancer Research and Treatment1292335. (doi:10.1007/s10549-010-1169-4).

    • Search Google Scholar
    • Export Citation
  • SimõesBMO'BrienCSEyreRSilvaAYuLSarmiento-CastroAAlferezDSpenceKSantiago-GómezAChemiF2015Anti-estrogen resistance in human breast tumors is driven by JAG1–NOTCH4-dependent cancer stem cell activity. Cell Reports1219681977. (doi:10.1016/j.celrep.2015.08.050).

    • Search Google Scholar
    • Export Citation
  • SpeirsVSklirisGPBurdallSECarderPJ2002Distinct expression patterns of ERα and ERβ in normal human mammary gland. Journal of Clinical Pathology55371374. (doi:10.1136/jcp.55.5.371).

    • Search Google Scholar
    • Export Citation
  • StylianouSClarkeRBBrennanK2006Aberrant activation of notch signaling in human breast cancer. Cancer Research6615171525. (doi:10.1158/0008-5472.CAN-05-3054).

    • Search Google Scholar
    • Export Citation
  • ThieryJP2002Epithelial–mesenchymal transitions in tumour progression. Nature Reviews. Cancer2442454. (doi:10.1038/nrc822).

  • TurnbullAKArthurLMRenshawLLarionovAAKayCDunbierAKThomasJSDowsettMSimsAHDixonJM2015Accurate prediction and validation of response to endocrine therapy in breast cancer. Journal of Clinical Oncology3322702278. (doi:10.1200/JCO.2014.57.8963).

    • Search Google Scholar
    • Export Citation
  • TurnerNCRoJAndreFLoiSVermaSIwataHHarbeckNLoiblSHuang BartlettCZhangK2015Palbociclib in hormone-receptor-positive advanced breast cancer. New England Journal of Medicine373209219. (doi:10.1056/NEJMoa1505270).

    • Search Google Scholar
    • Export Citation
  • VisvaderJELindemanGJ2012Cancer stem cells: current status and evolving complexities. Cell Stem Cell10717728. (doi:10.1016/j.stem.2012.05.007).

    • Search Google Scholar
    • Export Citation
  • WangZZhangXShenPLoggieBWChangYDeuelTF2005Identification, cloning, and expression of human estrogen receptor-α36, a novel variant of human estrogen receptor-α66. Biochemical and Biophysical Research Communications33610231027. (doi:10.1016/j.bbrc.2005.08.226).

    • Search Google Scholar
    • Export Citation
  • WangZZhangXShenPLoggieBWChangYDeuelTF2006A variant of estrogen receptor-{α}, hER-{α}36: transduction of estrogen- and antiestrogen-dependent membrane-initiated mitogenic signaling. PNAS10390639068. (doi:10.1073/pnas.0603339103).

    • Search Google Scholar
    • Export Citation
  • WidschwendterMRosenthalANPhilpottSRizzutoIFraserLHaywardJIntermaggioMPEdlundCKRamusSJGaytherSA2013The sex hormone system in carriers of BRCA1/2 mutations: a case–control study. Lancet. Oncology1412261232. (doi:10.1016/S1470-2045(13)70448-0).

    • Search Google Scholar
    • Export Citation
  • YagerJDDavidsonNE2006Estrogen carcinogenesis in breast cancer. New England Journal of Medicine354270282. (doi:10.1056/NEJMra050776).

  • YamajiDNaRFeuermannYPechholdSChenWRobinsonGWHennighausenL2009Development of mammary luminal progenitor cells is controlled by the transcription factor STAT5A. Genes and Development2323822387. (doi:10.1101/gad.1840109).

    • Search Google Scholar
    • Export Citation
  • YangMHWuMZChiouSHChenPMChangSYLiuCJTengSCWuKJ2008Direct regulation of TWIST by HIF-1α promotes metastasis. Nature Cell Biology10295305. (doi:10.1038/ncb1691).

    • Search Google Scholar
    • Export Citation
  • YuFLiJChenHFuJRaySHuangSZhengHAiW2011Kruppel-like factor 4 (KLF4) is required for maintenance of breast cancer stem cells and for cell migration and invasion. Oncogene3021612172. (doi:10.1038/onc.2010.591).

    • Search Google Scholar
    • Export Citation
  • ZhangPAndrianakosRYangYLiuCLuW2010Kruppel-like factor 4 (Klf4) prevents embryonic stem (ES) cell differentiation by regulating Nanog gene expression. Journal of Biological Chemistry28591809189. (doi:10.1074/jbc.M109.077958).

    • Search Google Scholar
    • Export Citation

This paper forms part of a thematic review section on Stem Cells and Cancer. The guest editor for this section was Dean Tang, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA.

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 1487 1008 30
PDF Downloads 420 294 16

Altmetrics

Figures

  • View in gallery

    Schematic representation of paracrine and juxtacrine signals involved in estrogen and progesterone regulation of BCSCs. Estrogen and progesterone bind estrogen receptor (ER) and progesterone receptor (PR) nuclear transcription factors, respectively, regulating expression of target genes. Estrogen sensor cells (non-BCSCs) increase transcription of epidermal growth factor (EGF), amphiregulin (AREG), transforming growth factor alpha (TGFα), and fibroblast growth factor (FGF), which will signal to the BCSCs through the EGFRs and FGFRs. Non-BCSCs can also signal to the BCSCs via Notch signalling. Progesterone sensor cells (non-BCSCs) also increase transcription of several important signalling factors. Progesterone regulation of BCSCs may occur via activation of RANK/RANKL, Wnt receptors/Wnt4, CXCR4/CXCL12, and GHR/GH paracrine signalling (dashed lines). Estrogen and progesterone-induced signals can be blocked by anti-estrogens (e.g. tamoxifen and fulvestrant) and anti-progesterone drugs (e.g. mifepristone and onapristone).

References

  • Al-HajjMWichaMSBenito-HernandezAMorrisonSJClarkeMF2003Prospective identification of tumorigenic breast cancer cells. PNAS10039833988. (doi:10.1073/pnas.0530291100).

    • Search Google Scholar
    • Export Citation
  • AliSCoombesRC2002Endocrine-responsive breast cancer and strategies for combating resistance. Nature Reviews. Cancer2101112. (doi:10.1038/nrc721).

    • Search Google Scholar
    • Export Citation
  • Asselin-LabatMLVaillantFSheridanJMPalBWuDSimpsonERYasudaHSmythGKMartinTJLindemanGJ2010Control of mammary stem cell function by steroid hormone signalling. Nature465798802. (doi:10.1038/nature09027).

    • Search Google Scholar
    • Export Citation
  • AxlundSDYooBHRosenRBSchaackJKabosPLabarberaDVSartoriusCA2013Progesterone-inducible cytokeratin 5-positive cells in luminal breast cancer exhibit progenitor properties. Hormones & Cancer43649. (doi:10.1007/s12672-012-0127-5).

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

    • Search Google Scholar
    • Export Citation
  • BeelenKZwartWLinnSC2012Can predictive biomarkers in breast cancer guide adjuvant endocrine therapy?Nature Reviews. Clinical Oncology9529541. (doi:10.1038/nrclinonc.2012.121).

    • Search Google Scholar
    • Export Citation
  • BocchinfusoWPKorachKS1997Mammary gland development and tumorigenesis in estrogen receptor knockout mice. Journal of Mammary Gland Biology and Neoplasia2323334. (doi:10.1023/A:1026339111278).

    • Search Google Scholar
    • Export Citation
  • BrennanKBrownAM2003Is there a role for Notch signalling in human breast cancer?Breast Cancer Research56975. (doi:10.1186/bcr559).

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

    • Search Google Scholar
    • Export Citation
  • CariatiMNaderiABrownJPSmalleyMJPinderSECaldasCPurushothamAD2008Alpha-6 integrin is necessary for the tumourigenicity of a stem cell-like subpopulation within the MCF7 breast cancer cell line. International Journal of Cancer122298304. (doi:10.1002/ijc.23103).

    • Search Google Scholar
    • Export Citation
  • Charafe-JauffretEGinestierCIovinoFTarpinCDiebelMEsterniBHouvenaeghelGExtraJMBertucciFJacquemierJ2010Aldehyde dehydrogenase 1-positive cancer stem cells mediate metastasis and poor clinical outcome in inflammatory breast cancer. Clinical Cancer Research164555. (doi:10.1158/1078-0432.CCR-09-1630).

    • Search Google Scholar
    • Export Citation
  • ChlebowskiRTAndersonGLGassMLaneDSAragakiAKKullerLHMansonJEStefanickMLOckeneJSartoGE2010Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. Journal of the American Medical Association30416841692. (doi:10.1001/jama.2010.1500).

    • Search Google Scholar
    • Export Citation
  • CittellyDMFinlay-SchultzJHoweENSpoelstraNSAxlundSDHendricksPJacobsenBMSartoriusCARicherJK2013Progestin suppression of miR-29 potentiates dedifferentiation of breast cancer cells via KLF4. Oncogene3225552564. (doi:10.1038/onc.2012.275).

    • Search Google Scholar
    • Export Citation
  • ClemonsMGossP2001Estrogen and the risk of breast cancer. New England Journal of Medicine344276285. (doi:10.1056/NEJM200101253440407).

    • Search Google Scholar
    • Export Citation
  • ColditzGA1998Relationship between estrogen levels, use of hormone replacement therapy, and breast cancer. Journal of the National Cancer Institute90814823. (doi:10.1093/jnci/90.11.814).

    • Search Google Scholar
    • Export Citation
  • CreightonCJChangJCRosenJM2010Epithelial–mesenchymal transition (EMT) in tumor-initiating cells and its clinical implications in breast cancer. Journal of Mammary Gland Biology and Neoplasia15253260. (doi:10.1007/s10911-010-9173-1).

    • Search Google Scholar
    • Export Citation
  • DengHZhangX-TWangM-LZhengH-YLiuL-JWangZ-Y2014ER-α36-mediated rapid estrogen signaling positively regulates ER-positive breast cancer stem/progenitor cells. PLoS ONE9e88034. (doi:10.1371/journal.pone.0088034).

    • Search Google Scholar
    • Export Citation
  • DontuGAbdallahWMFoleyJMJacksonKWClarkeMFKawamuraMJWichaMS2003In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes and Development1712531270. (doi:10.1101/gad.1061803).

    • Search Google Scholar
    • Export Citation
  • DowsettMNielsenTOA'HernRBartlettJCoombesRCCuzickJEllisMHenryNLHughJCLivelyT2011Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. Journal of the National Cancer Institute10316561664. (doi:10.1093/jnci/djr393).

    • Search Google Scholar
    • Export Citation
  • Early Breast Cancer Trialists' Collaborative GroupDaviesCGodwinJGrayRClarkeMCutterDDarbySMcGalePPanHCTaylorC2011Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet378771784. (doi:10.1016/S0140-6736(11)60993-8).

    • Search Google Scholar
    • Export Citation
  • EllisMJGaoFDehdashtiFJeffeDBMarcomPKCareyLADicklerMNSilvermanPFlemingGFKommareddyA2009Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study. Journal of the American Medical Association302774780. (doi:10.1001/jama.2009.1204).

    • Search Google Scholar
    • Export Citation
  • FarnieGClarkeRBSpenceKPinnockNBrennanKAndersonNGBundredNJ2007Novel cell culture technique for primary ductal carcinoma in situ: role of Notch and epidermal growth factor receptor signaling pathways. Journal of the National Cancer Institute99616627. (doi:10.1093/jnci/djk133).

    • Search Google Scholar
    • Export Citation
  • FehmTHoffmannOAktasBBeckerSSolomayerEFWallwienerDKimmigRKasimir-BauerS2009Detection and characterization of circulating tumor cells in blood of primary breast cancer patients by RT-PCR and comparison to status of bone marrow disseminated cells. Breast Cancer Research11R59. (doi:10.1186/bcr2349).

    • Search Google Scholar
    • Export Citation
  • FillmoreCMGuptaPBRudnickJACaballeroSKellerPJLanderESKuperwasserC2010Estrogen expands breast cancer stem-like cells through paracrine FGF/Tbx3 signaling. PNAS1072173721742. (doi:10.1073/pnas.1007863107).

    • Search Google Scholar
    • Export Citation
  • Finlay-SchultzJCittellyDMHendricksPPatelPKabosPJacobsenBMRicherJKSartoriusCA2014Progesterone downregulation of miR-141 contributes to expansion of stem-like breast cancer cells through maintenance of progesterone receptor and Stat5a. Oncogene3436763687. (doi:10.1038/onc.2014.298).

    • Search Google Scholar
    • Export Citation
  • FinnRSCrownJPLangIBoerKBondarenkoIMKulykSOEttlJPatelRPinterTSchmidtM2015The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet. Oncology162535. (doi:10.1016/S1470-2045(14)71159-3).

    • Search Google Scholar
    • Export Citation
  • GinestierCHurMHCharafe-JauffretEMonvilleFDutcherJBrownMJacquemierJViensPKleerCGLiuS2007ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell1555567. (doi:10.1016/j.stem.2007.08.014).

    • Search Google Scholar
    • Export Citation
  • Gonzalez-SuarezEJacobAPJonesJMillerRRoudier-MeyerMPErwertRPinkasJBranstetterDDougallWC2010RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature468103107. (doi:10.1038/nature09495).

    • Search Google Scholar
    • Export Citation
  • GrahamJDYagerMLHillHDBythKO'NeillGMClarkeCL2005Altered progesterone receptor isoform expression remodels progestin responsiveness of breast cancer cells. Molecular Endocrinology1927132735. (doi:10.1210/me.2005-0126).

    • Search Google Scholar
    • Export Citation
  • GrahamJDMotePASalagameUvan DijkJHBalleineRLHuschtschaLIReddelRRClarkeCL2009DNA replication licensing and progenitor numbers are increased by progesterone in normal human breast. Endocrinology15033183326. (doi:10.1210/en.2008-1630).

    • Search Google Scholar
    • Export Citation
  • HarrisonHFarnieGHowellSJRockREStylianouSBrennanKRBundredNJClarkeRB2010Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Research70709718. (doi:10.1158/0008-5472.CAN-09-1681).

    • Search Google Scholar
    • Export Citation
  • HarrisonHSimõesBMRogersonLHowellSJLandbergGClarkeRB2013Oestrogen increases the activity of oestrogen receptor negative breast cancer stem cells through paracrine EGFR and Notch signalling. Breast Cancer Research15R21. (doi:10.1186/bcr3396).

    • Search Google Scholar
    • Export Citation
  • HiltonHNSantucciNSilvestriAKantimmSHuschtschaLIGrahamJDClarkeCL2014Progesterone stimulates progenitor cells in normal human breast and breast cancer cells. Breast Cancer Research and Treatment143423433. (doi:10.1007/s10549-013-2817-2).

    • Search Google Scholar
    • Export Citation
  • HonethGBendahlPORingnerMSaalLHGruvberger-SaalSKLovgrenKGrabauDFernoMBorgAHegardtC2008The CD44+/CD24 phenotype is enriched in basal-like breast tumors. Breast Cancer Research10R53. (doi:10.1186/bcr2108).

    • Search Google Scholar
    • Export Citation
  • HowellARobertsonJFAbramPLichinitserMRElledgeRBajettaEWatanabeTMorrisCWebsterADimeryI2004Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: a multinational, double-blind, randomized trial. Journal of Clinical Oncology2216051613. (doi:10.1200/JCO.2004.02.112).

    • Search Google Scholar
    • Export Citation
  • HurtzCHatziKCerchiettiLBraigMParkEKimYMHerzogSRamezani-RadPJumaaHMullerMC2011BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia. Journal of Experimental Medicine20821632174. (doi:10.1084/jem.20110304).

    • Search Google Scholar
    • Export Citation
  • HutchesonIRKnowldenJMMaddenTABarrowDGeeJMWakelingAENicholsonRI2003Oestrogen receptor-mediated modulation of the EGFR/MAPK pathway in tamoxifen-resistant MCF-7 cells. Breast Cancer Research and Treatment818193. (doi:10.1023/A:1025484908380).

    • Search Google Scholar
    • Export Citation
  • IthimakinSDayKCMalikFZenQDawseySJBersano-BegeyTFQuraishiAAIgnatoskiKWDaignaultSDavisA2013HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification: implications for efficacy of adjuvant trastuzumab. Cancer Research7316351646. (doi:10.1158/0008-5472.CAN-12-3349).

    • Search Google Scholar
    • Export Citation
  • JoshiPAJacksonHWBeristainAGDi GrappaMAMotePAClarkeCLStinglJWaterhousePDKhokhaR2010Progesterone induces adult mammary stem cell expansion. Nature465803807. (doi:10.1038/nature09091).

    • Search Google Scholar
    • Export Citation
  • KabosPHaughianJMWangXDyeWWFinlaysonCEliasAHorwitzKBSartoriusCA2011Cytokeratin 5 positive cells represent a steroid receptor negative and therapy resistant subpopulation in luminal breast cancers. Breast Cancer Research and Treatment1284555. (doi:10.1007/s10549-010-1078-6).

    • Search Google Scholar
    • Export Citation
  • KastnerPKrustATurcotteBStroppUToraLGronemeyerHChambonP1990Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. EMBO Journal916031614.

    • Search Google Scholar
    • Export Citation
  • KnowldenJMHutchesonIRJonesHEMaddenTGeeJMHarperMEBarrowDWakelingAENicholsonRI2003Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells. Endocrinology14410321044. (doi:10.1210/en.2002-220620).

    • Search Google Scholar
    • Export Citation
  • KuiperGGLemmenJGCarlssonBCortonJCSafeSHvan der SaagPTvan der BurgBGustafssonJA1998Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor β. Endocrinology13942524263.

    • Search Google Scholar
    • Export Citation
  • LaCroixAZChlebowskiRTMansonJEAragakiAKJohnsonKCMartinLMargolisKLStefanickMLBrzyskiRCurbJD2011Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. Journal of the American Medical Association30513051314. (doi:10.1001/jama.2011.382).

    • Search Google Scholar
    • Export Citation
  • Lewis-WambiJSJordanVC2009Estrogen regulation of apoptosis: how can one hormone stimulate and inhibit?Breast Cancer Research11206. (doi:10.1186/bcr2255).

    • Search Google Scholar
    • Export Citation
  • LiXLewisMTHuangJGutierrezCOsborneCKWuMFHilsenbeckSGPavlickAZhangXChamnessGC2008Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. Journal of the National Cancer Institute100672679. (doi:10.1093/jnci/djn123).

    • Search Google Scholar
    • Export Citation
  • LiuRWangXChenGYDalerbaPGurneyAHoeyTSherlockGLewickiJSheddenKClarkeMF2007The prognostic role of a gene signature from tumorigenic breast-cancer cells. New England Journal of Medicine356217226. (doi:10.1056/NEJMoa063994).

    • Search Google Scholar
    • Export Citation
  • LiuSCongYWangDSunYDengLLiuYMartin-TrevinoRShangLMcDermottSPLandisMD2014Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Reports27891. (doi:10.1016/j.stemcr.2013.11.009).

    • Search Google Scholar
    • Export Citation
  • LombardiSHonethGGinestierCShinomiyaIMarlowRBuchupalliBGazinskaPBrownJCatchpoleSLiuS2014Growth hormone is secreted by normal breast epithelium upon progesterone stimulation and increases proliferation of stem/progenitor cells. Stem Cell Reports2780793. (doi:10.1016/j.stemcr.2014.05.005).

    • Search Google Scholar
    • Export Citation
  • LydonJPDeMayoFJFunkCRManiSKHughesARMontgomeryCAJrShyamalaGConneelyOMO'MalleyBW1995Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes and Development922662278. (doi:10.1101/gad.9.18.2266).

    • Search Google Scholar
    • Export Citation
  • LydonJPGeGKittrellFSMedinaDO'MalleyBW1999Murine mammary gland carcinogenesis is critically dependent on progesterone receptor function. Cancer Research5942764284.

    • Search Google Scholar
    • Export Citation
  • McClellandRABarrowDMaddenTADutkowskiCMPammentJKnowldenJMGeeJMNicholsonRI2001Enhanced epidermal growth factor receptor signaling in MCF7 breast cancer cells after long-term culture in the presence of the pure antiestrogen ICI 182,780 (Faslodex). Endocrinology14227762788.

    • Search Google Scholar
    • Export Citation
  • MedinaD2004Breast cancer: the protective effect of pregnancy. Clinical Cancer Research10380S384S. (doi:10.1158/1078-0432.CCR-031211).

    • Search Google Scholar
    • Export Citation
  • Miranda-LorenzoIDoradoJLonardoEAlcalaSSerranoAGClausell-TormosJCioffiMMegiasDZagoracSBalicA2014Intracellular autofluorescence: a biomarker for epithelial cancer stem cells. Nature Methods1111611169. (doi:10.1038/nmeth.3112).

    • Search Google Scholar
    • Export Citation
  • MokbelK2002The evolving role of aromatase inhibitors in breast cancer. International Journal of Clinical Oncology7279283.

  • MorimotoKKimSJTaneiTShimazuKTanjiYTaguchiTTamakiYTeradaNNoguchiS2009Stem cell marker aldehyde dehydrogenase 1-positive breast cancers are characterized by negative estrogen receptor, positive human epidermal growth factor receptor type 2, and high Ki67 expression. Cancer Science10010621068. (doi:10.1111/j.1349-7006.2009.01151.x).

    • Search Google Scholar
    • Export Citation
  • MotePABartowSTranNClarkeCL2002Loss of co-ordinate expression of progesterone receptors A and B is an early event in breast carcinogenesis. Breast Cancer Research and Treatment72163172. (doi:10.1023/A:1014820500738).

    • Search Google Scholar
    • Export Citation
  • Mulac-JericevicBMullinaxRADeMayoFJLydonJPConneelyOM2000Subgroup of reproductive functions of progesterone mediated by progesterone receptor-B isoform. Science28917511754. (doi:10.1126/science.289.5485.1751).

    • Search Google Scholar
    • Export Citation
  • Mulac-JericevicBLydonJPDeMayoFJConneelyOM2003Defective mammary gland morphogenesis in mice lacking the progesterone receptor B isoform. PNAS10097449749. (doi:10.1073/pnas.1732707100).

    • Search Google Scholar
    • Export Citation
  • MusgroveEASutherlandRL2009Biological determinants of endocrine resistance in breast cancer. Nature Reviews. Cancer9631643. (doi:10.1038/nrc2713).

    • Search Google Scholar
    • Export Citation
  • NarodSA2011Hormone replacement therapy and the risk of breast cancer. Nature Reviews. Clinical Oncology8669676. (doi:10.1038/nrclinonc.2011.110).

    • Search Google Scholar
    • Export Citation
  • NavarreteMAMaierCMFalzoniRQuadrosLGLimaGRBaracatECNazarioAC2005Assessment of the proliferative, apoptotic and cellular renovation indices of the human mammary epithelium during the follicular and luteal phases of the menstrual cycle. Breast Cancer Research7R306R313. (doi:10.1186/bcr994).

    • Search Google Scholar
    • Export Citation
  • PalafoxMFerrerIPellegriniPVilaSHernandez-OrtegaSUrruticoecheaAClimentFSolerMTMunozPVinalsF2012RANK induces epithelial–mesenchymal transition and stemness in human mammary epithelial cells and promotes tumorigenesis and metastasis. Cancer Research7228792888. (doi:10.1158/0008-5472.CAN-12-0044).

    • Search Google Scholar
    • Export Citation
  • PatrawalaLCalhounTSchneider-BroussardRZhouJClaypoolKTangDG2005Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2 cancer cells are similarly tumorigenic. Cancer Research6562076219. (doi:10.1158/0008-5472.CAN-05-0592).

    • Search Google Scholar
    • Export Citation
  • PeceSTosoniDConfalonieriSMazzarolGVecchiMRonzoniSBernardLVialeGPelicciPGDi FiorePP2010Biological and molecular heterogeneity of breast cancers correlates with their cancer stem cell content. Cell1406273. (doi:10.1016/j.cell.2009.12.007).

    • Search Google Scholar
    • Export Citation
  • PerouCMSorlieTEisenMBvan de RijnMJeffreySSReesCAPollackJRRossDTJohnsenHAkslenLA2000Molecular portraits of human breast tumours. Nature406747752. (doi:10.1038/35021093).

    • Search Google Scholar
    • Export Citation
  • PetersenOWHoyerPEvan DeursB1987Frequency and distribution of estrogen receptor-positive cells in normal, nonlactating human breast tissue. Cancer Research4757485751.

    • Search Google Scholar
    • Export Citation
  • PhillipsTMMcBrideWHPajonkF2006The response of CD24(−/low)/CD44+ breast cancer-initiating cells to radiation. Journal of the National Cancer Institute9817771785. (doi:10.1093/jnci/djj495).

    • Search Google Scholar
    • Export Citation
  • PivaMDomeniciGIriondoORabanoMSimõesBMComaillsVBarredoILopez-RuizJAZabalzaIKyptaR2014Sox2 promotes tamoxifen resistance in breast cancer cells. EMBO Molecular Medicine66679. (doi:10.1002/emmm.201303411).

    • Search Google Scholar
    • Export Citation
  • PontiDCostaAZaffaroniNPratesiGPetrangoliniGCoradiniDPilottiSPierottiMADaidoneMG2005Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Research6555065511. (doi:10.1158/0008-5472.CAN-05-0626).

    • Search Google Scholar
    • Export Citation
  • PooleAJLiYKimYLinSCLeeWHLeeEY2006Prevention of Brca1-mediated mammary tumorigenesis in mice by a progesterone antagonist. Science31414671470. (doi:10.1126/science.1130471).

    • Search Google Scholar
    • Export Citation
  • PottenCSWatsonRJWilliamsGTTickleSRobertsSAHarrisMHowellA1988The effect of age and menstrual cycle upon proliferative activity of the normal human breast. British Journal of Cancer58163170. (doi:10.1038/bjc.1988.185).

    • Search Google Scholar
    • Export Citation
  • RajkumarLGuzmanRCYangJThordarsonGTalamantesFNandiS2001Short-term exposure to pregnancy levels of estrogen prevents mammary carcinogenesis. PNAS981175511759. (doi:10.1073/pnas.201393798).

    • Search Google Scholar
    • Export Citation
  • ReyaTMorrisonSJClarkeMFWeissmanIL2001Stem cells, cancer, and cancer stem cells. Nature414105111. (doi:10.1038/35102167).

  • RicherJKJacobsenBMManningNGAbelMGWolfDMHorwitzKB2002Differential gene regulation by the two progesterone receptor isoforms in human breast cancer cells. Journal of Biological Chemistry27752095218. (doi:10.1074/jbc.M110090200).

    • Search Google Scholar
    • Export Citation
  • RussoJMoralRBaloghGAMailoDRussoIH2005The protective role of pregnancy in breast cancer. Breast Cancer Research7131142. (doi:10.1186/bcr1029).

    • Search Google Scholar
    • Export Citation
  • SatoTTranTHPeckARGirondoMALiuCGoodmanCRNeilsonLMFreydinBChervonevaIHyslopT2014Prolactin suppresses a progestin-induced CK5-positive cell population in luminal breast cancer through inhibition of progestin-driven BCL6 expression. Oncogene3322152224. (doi:10.1038/onc.2013.172).

    • Search Google Scholar
    • Export Citation
  • SchramekDLeibbrandtASiglVKennerLPospisilikJALeeHJHanadaRJoshiPAAliprantisAGlimcherL2010Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature46898102. (doi:10.1038/nature09387).

    • Search Google Scholar
    • Export Citation
  • ShiahYJTharmapalanPCaseyAEJoshiPAMcKeeTDJacksonHWBeristainAGChan-Seng-YueMABaderGDLydonJP2015A progesterone–CXCR4 axis controls mammary progenitor cell fate in the adult gland. Stem Cell Reports4313322. (doi:10.1016/j.stemcr.2015.01.011).

    • Search Google Scholar
    • Export Citation
  • ShiauAKBarstadDLoriaPMChengLKushnerPJAgardDAGreeneGL1998The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell95927937. (doi:10.1016/S0092-8674(00)81717-1).

    • Search Google Scholar
    • Export Citation
  • SimõesBMVivancoMD2011Cancer stem cells in the human mammary gland and regulation of their differentiation by estrogen. Future Oncology79951006. (doi:10.2217/fon.11.80).

    • Search Google Scholar
    • Export Citation
  • SimõesBMPivaMIriondoOComaillsVLopez-RuizJAZabalzaIMiezaJAAcinasOVivancoMD2011Effects of estrogen on the proportion of stem cells in the breast. Breast Cancer Research and Treatment1292335. (doi:10.1007/s10549-010-1169-4).

    • Search Google Scholar
    • Export Citation
  • SimõesBMO'BrienCSEyreRSilvaAYuLSarmiento-CastroAAlferezDSpenceKSantiago-GómezAChemiF2015Anti-estrogen resistance in human breast tumors is driven by JAG1–NOTCH4-dependent cancer stem cell activity. Cell Reports1219681977. (doi:10.1016/j.celrep.2015.08.050).

    • Search Google Scholar
    • Export Citation
  • SpeirsVSklirisGPBurdallSECarderPJ2002Distinct expression patterns of ERα and ERβ in normal human mammary gland. Journal of Clinical Pathology55371374. (doi:10.1136/jcp.55.5.371).

    • Search Google Scholar
    • Export Citation
  • StylianouSClarkeRBBrennanK2006Aberrant activation of notch signaling in human breast cancer. Cancer Research6615171525. (doi:10.1158/0008-5472.CAN-05-3054).

    • Search Google Scholar
    • Export Citation
  • ThieryJP2002Epithelial–mesenchymal transitions in tumour progression. Nature Reviews. Cancer2442454. (doi:10.1038/nrc822).

  • TurnbullAKArthurLMRenshawLLarionovAAKayCDunbierAKThomasJSDowsettMSimsAHDixonJM2015Accurate prediction and validation of response to endocrine therapy in breast cancer. Journal of Clinical Oncology3322702278. (doi:10.1200/JCO.2014.57.8963).

    • Search Google Scholar
    • Export Citation
  • TurnerNCRoJAndreFLoiSVermaSIwataHHarbeckNLoiblSHuang BartlettCZhangK2015Palbociclib in hormone-receptor-positive advanced breast cancer. New England Journal of Medicine373209219. (doi:10.1056/NEJMoa1505270).

    • Search Google Scholar
    • Export Citation
  • VisvaderJELindemanGJ2012Cancer stem cells: current status and evolving complexities. Cell Stem Cell10717728. (doi:10.1016/j.stem.2012.05.007).

    • Search Google Scholar
    • Export Citation
  • WangZZhangXShenPLoggieBWChangYDeuelTF2005Identification, cloning, and expression of human estrogen receptor-α36, a novel variant of human estrogen receptor-α66. Biochemical and Biophysical Research Communications33610231027. (doi:10.1016/j.bbrc.2005.08.226).

    • Search Google Scholar
    • Export Citation
  • WangZZhangXShenPLoggieBWChangYDeuelTF2006A variant of estrogen receptor-{α}, hER-{α}36: transduction of estrogen- and antiestrogen-dependent membrane-initiated mitogenic signaling. PNAS10390639068. (doi:10.1073/pnas.0603339103).

    • Search Google Scholar
    • Export Citation
  • WidschwendterMRosenthalANPhilpottSRizzutoIFraserLHaywardJIntermaggioMPEdlundCKRamusSJGaytherSA2013The sex hormone system in carriers of BRCA1/2 mutations: a case–control study. Lancet. Oncology1412261232. (doi:10.1016/S1470-2045(13)70448-0).

    • Search Google Scholar
    • Export Citation
  • YagerJDDavidsonNE2006Estrogen carcinogenesis in breast cancer. New England Journal of Medicine354270282. (doi:10.1056/NEJMra050776).

  • YamajiDNaRFeuermannYPechholdSChenWRobinsonGWHennighausenL2009Development of mammary luminal progenitor cells is controlled by the transcription factor STAT5A. Genes and Development2323822387. (doi:10.1101/gad.1840109).

    • Search Google Scholar
    • Export Citation
  • YangMHWuMZChiouSHChenPMChangSYLiuCJTengSCWuKJ2008Direct regulation of TWIST by HIF-1α promotes metastasis. Nature Cell Biology10295305. (doi:10.1038/ncb1691).

    • Search Google Scholar
    • Export Citation
  • YuFLiJChenHFuJRaySHuangSZhengHAiW2011Kruppel-like factor 4 (KLF4) is required for maintenance of breast cancer stem cells and for cell migration and invasion. Oncogene3021612172. (doi:10.1038/onc.2010.591).

    • Search Google Scholar
    • Export Citation
  • ZhangPAndrianakosRYangYLiuCLuW2010Kruppel-like factor 4 (Klf4) prevents embryonic stem (ES) cell differentiation by regulating Nanog gene expression. Journal of Biological Chemistry28591809189. (doi:10.1074/jbc.M109.077958).

    • Search Google Scholar
    • Export Citation

Cited By

PubMed

Google Scholar