Adjuvant radiotherapy and adjuvant endocrine therapy are commonly given to patients with invasive breast cancer or with ductal carcinoma in situ (DCIS). Although both therapies have been well established through a number of randomized studies, little is known about a possible interaction of both treatment modalities if they are given simultaneously. A number of in vitro studies have indicated that tamoxifen treatment might reduce the intrinsic radiosensitivity of MCF-7 breast cancer cells. Conversely, estradiol treatment increases the intrinsic radiosensitivity of MCF-7 cells. In one available animal study, an antagonistic effect of tamoxifen and ionizing radiation (XRT) could not be observed. Retrospective analyses of randomized clinical studies have not indicated an antagonistic effect of tamoxifen on the effectiveness of XRT, since local control has been consistently higher when XRT was combined with tamoxifen, compared with treatment with XRT alone, regardless of whether tamoxifen was started simultaneously with radiotherapy or after completion of radiotherapy. Currently there are no clinical data available that would suggest an adverse effect of adjuvant tamoxifen treatment started prior to or simultaneously with radiotherapy in breast cancer or DCIS. However, since an antagonistic effect of tamoxifen and simultaneous chemotherapy has been reported recently, the issue of simultaneous versus sequential radiation and tamoxifen treatment in breast cancer should be addressed in further studies.
H Schmidberger, R M Hermann, C F Hess, and G Emons
Rebecca B Riggins, Mary M Mazzotta, Omar Z Maniya, and Robert Clarke
Nuclear receptors comprise a large family of highly conserved transcription factors that regulate many key processes in normal and neoplastic tissues. Most nuclear receptors share a common, highly conserved domain structure that includes a carboxy-terminal ligand-binding domain. However, a subgroup of this gene family is known as the orphan nuclear receptors because to date there are no known natural ligands that regulate their activity. Many of the 25 nuclear receptors classified as orphan play critical roles in embryonic development, metabolism, and the regulation of circadian rhythm. Here, we review the emerging role(s) of orphan nuclear receptors in breast cancer, with a particular focus on two of the estrogen-related receptors (ERRα and ERRγ) and several others implicated in clinical outcome and response or resistance to cytotoxic or endocrine therapies, including the chicken ovalbumin upstream promoter transcription factors, nerve growth factor-induced B, DAX-1, liver receptor homolog-1, and retinoic acid-related orphan receptor α. We also propose that a clearer understanding of the function of orphan nuclear receptors in mammary gland development and normal mammary tissues could significantly improve our ability to diagnose, treat, and prevent breast cancer.
There is definitely a need for the development of new drugs for the treatment and cure of endometrial cancer. In addition there are various new drugs or phyto-remedies under development which are intended for use in the treatment and prevention of breast cancer, for the treatment of menopausal symptoms and for hormone replacement therapy. The efficacy of novel drugs targeting steroid receptors in endometrial cancers has to be evaluated and the safety of other endocrine measures on endometrial cancers or on endometrial carcinogenesis has to be assessed. For these experimental purposes five main classes of experimental models are available: spontaneous endometrial tumorigenesis models in inbred animals (Donryu rats, DA/Han rats, BDII/Han rats), inoculation tumors from chunks of tumors (rat EnDA-tumor, human EnCa 101 tumor) or from inoculated tumor cell lines (rat RUCA-I cells, human Ishikawa and ECC-1 cells), developmental estrogenic exposure or chemical carcinogen exposure of CD-1 and ICR mice, transgenic approaches such as mice heterozygous regarding the tumor suppressor gene PTEN (pten(+/-)-mice) and endometrial tumor cell lines cultured under conditions promoting in vivo-like morphology and functions e.g. cell culture on reconstituted basement membrane. Although the number of models is comparatively small, most aspects related to functions of estrogenic or gestagenic substances are assessable, particularly if various experimental models are combined. Whereas models based on human endometrial adenocarcinoma cells are widely used, the properties and advantages of animal-derived models have mainly been ignored so far.
R M O'Regan and F R Khuri
The ras family of proto-oncogenes are upstream mediators of several essential cellular signal transduction pathways involved in cell proliferation and survival. Point mutations of ras oncogenes result in constitutively active Ras and have been shown to be oncogenic. However, ras activation can occur in the absence of ras mutations secondary to upstream receptor activation. The first important step in Ras activation is farnesylation by farnesyl transferase, and inhibitors of this enzyme have been demonstrated to inhibit Ras signaling, and have anti-tumor effects. However, it is now clear that farnesyl transferase inhibitors (FTIs) have activity independent of Ras, most likely due to effects on prenylated proteins downstream of Ras, which explains their activity in several malignancies, including breast cancer, where ras mutations are rare. Several FTIs are in clinical development for the treatment of solid tumors. Preclinical evidence suggests that FTIs can inhibit breast cancers in vitro and in vivo, and a phase II trial of the FTI, R115777, in patients with advanced breast cancer produced encouraging results. Based on prior successful outcomes with agents targeting the estrogen and epidermal growth factor receptor pathways in breast cancer, the FTIs, used alone or more likely with other agents, may be the next exciting targeted therapy in breast cancer.
Emmanuelle Fleurot, Caroline Goudin, Vincent Hanoux, Pierre-Jacques Bonnamy, and Jérôme Levallet
Breast cancer (BC) is the primary cause of cancer-related mortality among women. Patients who express the estrogen receptor (ER), which mediates the tumorigenic effects of estrogens, respond to antihormonal therapy. Loss of ER expression or acquired resistance to E2 is associated with aggressive malignant phenotypes, which lead to relapse. These BC subtypes overexpress syndecan-1 (SDC1), a transmembrane heparan sulfate proteoglycan that mediates angiogenesis as well as the proliferation and invasiveness of cancer cells. We showed here that the activation of ER-alpha (ERα) by estrogens induces downregulation of SDC1 expression in ER(+) MCF7 cells but not in T47D cells. Loss of ERα expression, induced by RNA interference or a selective ER downregulator, led to subsequent SDC1 overexpression. E2-dependent downregulation of SDC1 expression required de novo protein synthesis and was antagonized by treatment with BAY 11-7085, an irreversible inhibitor of IκBα phosphorylation, which inhibits the activation of NFκB. Downregulation of SDC1 expression required ERα and activation of IKK, but was independent to downstream transcriptional regulators of NFκB. BAY 11-7085 prevented E2-mediated phosphorylation of ERα on Ser118, increasing its proteasomal degradation, suggesting that IKK stabilized E2-activated ERα, leading to subsequent downregulation of SDC1 expression. Our results showed that sustained ER signaling inhibits SDC1 expression. Such antagonism elucidates the inverse correlation between SDC1 and ER expression in ER(+) BC as well as the overexpression of SDC1 in hormone receptor-negative BC subtypes with the most aggressive phenotypes. These results identify SDC1 as an attractive therapeutic target for BC as well as for other endocrine-associated cancers.
Nicola Normanno, Alessandro Morabito, Antonella De Luca, Maria Carmela Piccirillo, Marianna Gallo, Monica R Maiello, and Francesco Perrone
Identification of molecular alterations in key proteins involved in breast cancer cell proliferation and survival resulted in the development of a new treatment strategy with target-based agents. The anti-ErbB-2 monoclonal antibody (mAb) trastuzumab and the dual epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor lapatinib are effective in patients with breast cancer that overexpresses ErbB-2. The anti-vascular endothelial growth factor-A mAb bevacizumab is approved in combination with taxanes for treatment of unselected patients with metastatic breast cancer. In addition, preclinical data suggest that signaling inhibitors can prevent or overcome resistance to endocrine therapy in estrogen receptor positive (ER+) breast cancer. However, the majority of signaling inhibitors explored in breast cancer patients has shown little activity, at least when used as monotherapy; and the results of clinical trials in ER+ breast cancer of combinations of signaling inhibitors and endocrine therapies are rather disappointing. Negative findings are likely due to mechanisms of intrinsic or acquired resistance to target-based agents. Breast carcinoma is a complex and heterogeneous disease and several different molecular alterations are involved in its pathogenesis and progression. The redundancy of oncogenic pathways activated in cancer cells, the heterogeneity of the mechanisms of resistance, and the plasticity of tumor cells that are capable to adapt to different growth conditions, significantly hamper the efficacy of each signaling inhibitor in breast cancer. Therefore, a comprehensive approach that takes into account the complexity of the disease is definitely required to improve the efficacy of target-based therapy in breast cancer.
Vanessa W Lim, Jun Li, Yinhan Gong, Aizhen Jin, Jian-Min Yuan, Eu Leong Yong, and Woon-Puay Koh
The estrogen levels of Asian women are different from those of Western women, and this could affect estrogen receptor (ER) bioactivity and breast cancer risk. We conducted a case–control study in 169 postmenopausal breast cancer cases and 426 matched controls nested within a population-based prospective cohort study, the Singapore Chinese Health Study, to evaluate the serum levels of estrogens and their receptor (ERα and ERβ)-mediated estrogenic activities in relation to breast cancer risk. Breast cancer cases had higher levels of estrogens and ER-mediated bioactivities in baseline serum than the controls. Compared with those in the lowest quartile, women in the highest quartile for estrone (E1) or ERα-mediated bioactivity had increased breast cancer risk. After additional adjustment for ERβ bioactivity, free estradiol, and E1 levels, serum ERα-mediated bioactivity remained associated with increased breast cancer risk. Compared with those in the lowest quartile, women in the highest quartile for ERα-mediated bioactivity had an odds ratio of 2.39 (95% CI=1.17–4.88; P for trend=0.016). Conversely, the positive association between E1 and cancer risk became null after adjustment for ERα-mediated bioactivity, suggesting that the effect of E1 could be mediated through ERα. Factor(s) contributing to increased ERα-mediated estrogenic bioactivity in serum and its role as a predictor for breast cancer risk need to be validated in future studies.
Richard J Santen, Norman F Boyd, Rowan T Chlebowski, Steven Cummings, Jack Cuzick, Mitch Dowsett, Douglas Easton, John F Forbes, Tim Key, Susan E Hankinson, Anthony Howell, and James Ingle
The majority of candidates for breast cancer prevention have not accepted tamoxifen because of the perception of an unfavorable risk/benefit ratio and the acceptance of raloxifene remains to be determined. One means of improving this ratio is to identify women at very high risk of breast cancer. Family history, age, atypia in a benign biopsy, and reproductive factors are the main parameters currently used to determine risk. The most powerful risk factor, mammographic density, is not presently employed routinely. Other potentially important factors are plasma estrogen and androgen levels, bone density, weight gain, age of menopause, and fracture history, which are also not currently used in a comprehensive risk prediction model because of lack of prospective validation. The Breast Cancer Prevention Collaborative Group (BCPCG) met to critically examine and prioritize risk factors that might be selected for further testing by multivariate analysis using existing clinical material. The BCPCG reached a consensus that quantitative breast density, state of the art plasma estrogen and androgen measurements, history of fracture and height loss, BMI, and waist–hip ratio had sufficient priority for further testing. As a practical approach, these parameters could be added to the existing Tyrer–Cuzick model which encompasses factors included in both the Claus and Gail models. The BCPCG analyzed potentially available clinical material from previous prospective studies and determined that a large case/control study to evaluate these new factors might be feasible at this time.
R J Santen
Mathieu Lupien and Myles Brown
Alterations in transcription programs are a fundamental feature of cancer. Nuclear receptors, such as the estrogen receptor alpha (ERα) and androgen receptors (ARs), are central in this process as they can directly impact gene expression through interaction with the chromatin and subsequent association with coregulators and the transcriptional machinery. Unbiased genome-wide investigations have demonstrated the predominant recruitment of both ERα and AR to distant (non-promoter)-regulatory elements. Furthermore, these studies revealed a clear relationship between sites of transcription factor recruitment and gene regulation. Indeed, expression profiles from AR-positive primary prostate tumors and cell lines directly relate to the AR cistrome in prostate cancer cells, while the ERα cistrome in breast cancer cells relates to expression profiles from ERα-positive primary breast tumors. Additionally, cell-type-specific ERα cistromes are linked to lineage-specific estrogen-induced expression profiles in different cell types, for example osteosarcoma and breast cancer cells. The pioneer factor forkhead box A1 (FoxA1/HNF3α) plays a central role in AR and ERα signaling. It is recruited in a lineage-specific manner translating the epigenetic signature consisting of mono- and dimethylated histone H3 on lysine 4 (H3K4me1/me2) into functional regulatory elements. Hence, through the interplay between the pioneer factor, namely FoxA1, and epigenetic events, the transcriptional potential of a given cell lineage is predefined. Since this directly impacts signaling through nuclear receptors, these discoveries should significantly impact the development of novel therapeutic strategies directed against multiple types of cancer.