Molecular and Cellular Endocrinology 418 (2015) 240e244

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Review

Estrogen receptors in breast carcinogenesis and endocrine therapy Bo Huang a, Margaret Warner a, Jan-Åke Gustafsson a, b, * a

Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, 3605 Cullen Blvd, Science & Engineering Research Center Bldg 545, Houston, Texas 77204, USA b Department of Biosciences and Nutrition, Karolinska Institutet, Novum, Huddinge, Sweden

a r t i c l e i n f o

a b s t r a c t

Article history: Received 27 August 2014 Received in revised form 17 November 2014 Accepted 18 November 2014 Available online 26 November 2014

Excessive exposure to estrogen has long been associated with an increased risk for developing breast cancer and anti-estrogen therapy is the gold standard of care in the treatment of estrogen receptor (ER) a-positive breast cancers. However, there are several mysteries concerning both anti-estrogen, tamoxifen, and estrogen. The most important of these are: (1) some ERa-positive breast cancers do not respond to tamoxifen; (2) some ERa-negative breast cancers do respond to tamoxifen; (3) initial or acquired resistance to tamoxifen occurs with recurrent tumors; (4) estrogen can cause marked tumor regression in long-term tamoxifen-resistant ERa-positive breast cancer. These mysteries indicate that we do not know enough about estrogen signaling to understand the effects of targeting these receptors in cancer. The discovery of ERb, the second estrogen receptor, has added another level of complexity to estrogen signaling. This review summarizes recent publications and makes an updated portrait of ERa and ERb in breast carcinogenesis and endocrine cancer therapy. © 2014 Elsevier Ireland Ltd. All rights reserved.

Keywords: Estrogen receptor b Invasive ductal carcinoma Lobular cancer Tumor infiltrating leukocytes ERb-selective agonist

Contents 1.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240 1.1. Estrogen receptors in breast carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 1.1.1. ERs in normal mammary gland and breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 1.1.2. ERs in different stages of ductal breast carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 1.1.3. ERs in lobular breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 1.1.4. ERs in breast cancer microenvironment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 1.2. Endocrine therapy targeting ERs for breast cancer treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242 Conclusion and future direction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243

1. Introduction Most of the effects of estrogen are mediated through its two receptors: estrogen receptor alpha (ERa) and beta (ERb). ERa has been extensively studied in breast cancer. The protein is expressed

* Corresponding author. Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, 3605 Cullen Blvd, Science & Engineering Research Center Bldg 545, Houston, Texas, USA. Tel.: þ1 832. 842. 8803; fax: þ1 713. 743. 0634. E-mail address: [email protected] (J.-Å. Gustafsson). http://dx.doi.org/10.1016/j.mce.2014.11.015 0303-7207/© 2014 Elsevier Ireland Ltd. All rights reserved.

in 50e80% of breast tumors and is a good indicator for the success of hormone therapy. After almost 20 years since its discovery, the role of ERb in breast cancer is still being explored (Leygue and Murphy, 2013). ERb is more abundant than ERa in normal human and mouse mammary gland (Cheng et al., 2013; Huang et al., 2014). In ERa knockout mice, the breast is atrophic; while in ERb knockout mice, epithelium is hyperproliferative. These mouse studies are consistent with research from in vitro cell culture and from immunohistochemical studies, which have suggested the anti-ERa and tumor-suppressor functions of ERb. The present review will focus

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on the recent achievements from clinical and mouse studies. We will also discuss the current predicaments in applying endocrine therapy targeting estrogen receptors for treatment of breast cancer and provide prospective for future research. 1.1. Estrogen receptors in breast carcinogenesis At both the clinical and molecular level, breast cancer is a complex, heterogeneous disorder. If we are going to design curative pharmaceuticals, we need to better understand the signaling pathways involved in normal development of mammary gland and how dysregulation of these pathways leads to development of cancer. Estrogen/ER signaling is clearly important in normal mammary gland development and breast carcinogenesis. We will discuss this signaling pathway in more detail in the following paragraphs. 1.1.1. ERs in normal mammary gland and breast cancer Although much research has been done to decipher the role of ERs in mouse mammary gland development, we still do not understand how ERs work during human mammary gland development. In the last decade, some key developments have occurred which have filled in some of the gaps in our knowledge of estrogen signaling. In premenopausal women, ERa was localized mostly to the inner layer of epithelial cells lining acini and intralobular ducts, and to myoepithelial cells scattered in the external layer of interlobular ducts. ERb was more widespread, in epithelial as well as stromal cells (Li et al., 2010). In postmenopausal women, ERa is expressed in less than 10% of normal mammary epithelial cells, while ERb is expressed in more than 50% of normal mammary epithelial cells. Similar to the result from premenopausal women, stromal cells in postmenopausal women express nuclear ERb, but not ERa (Cheng et al., 2013). From mouse work we know that ERa is responsible for the proliferative effect of estrogen but this is not a direct effect. It occurs through a paracrine mechanism involving non-proliferating ERa-positive cells (Brisken and O’Malley, 2010). ERb represses proliferation and is pro-apoptotic (Thomas and Gustafsson, 2011). The breast is one of the few organs that undergoes the majority of its development after birth, so these results from normal mammary gland give us very fundamental insights about how ERs function normally and also provide some indications for understanding of what can go wrong during cancer initiation and progression. Many studies have demonstrated a correlation between ERa and ERb status with breast cancer survival outcomes (see recent reviews (Burns and Korach, 2012; Leygue and Murphy, 2013; Thomas and Gustafsson, 2011; Warner and Gustafsson, 2010)). ERa is considered to be a good indicator for endocrine therapy and breast cancer survival. Loss of ERa in breast cancer patients indicates invasiveness and poor prognosis (Herynk and Fuqua, 2007). Many labs have reported on ERb expression in clinical samples (Bozkurt and Kapucuoglu, 2012; Esslimani-Sahla et al., 2004; Fuqua et al., 2003; Gruvberger-Saal et al., 2007; Jarvinen et al., 2000; Miller et al., 2006; Miyoshi et al., 2001; Omoto et al., 2002; O’Neill et al., 2004; Roger et al., 2001; Saunders et al., 2002; Shaaban et al., 2003; Shaw et al., 2002; Skliris et al., 2001, 2003, 2006; Speirs et al., 1999; Sugiura et al., 2007). Some, but not all, have linked high ERb expression with better prognosis. Cell lines and pre-clinical breast cancer animal model studies also suggest a beneficial effect of ERb (Murphy and Leygue, 2012; Warner and Gustafsson, 2010). 1.1.2. ERs in different stages of ductal breast carcinogenesis Breast cancers are now classified according to gene expression profiles into luminal A (ERa and PR positive, low proliferation rate), luminal B (ERa- and PR-positive, high proliferation rate), HER2overexpressing, and triple-negative carcinoma (TNC) which

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expresses neither ERa, PR or HER2. Clearly, this classification is based on the well-known receptors traditionally studied in breast cancer and will have to be modified as we learn more about other targetable receptors in breast cancer. In addition, this classification does not place lobular cancer and does not consider the tumor environment whose importance in invasiveness of breast cancer is becoming more recognized. According to the “old” classification, approximately 80% of all breast cancer cases are ductal cancer while 10% are lobular cancers (Korhonen et al., 2004). Ductal cancers are well-studied and they are known to occur in stages progressing from normal terminal duct lobular unit (TDLU) to ductal carcinoma in situ (DCIS) and then finally to invasive ductal carcinoma (IDC) (Wellings and Jensen, 1973). DCIS is defined as non-invasive cancer, which has not spread beyond the duct into any normal surrounding breast tissue and is thought to be the direct precursor of IDC (Burstein et al., 2004; Sgroi, 2010). No genetic events have been identified to explain the transition of DCIS to IDC (Polyak, 2007). Investigation of the expression pattern of ERa and ERb in normal tissue, DCIS and IDC is a first step in understanding the function of these two receptors in the progression of breast cancer. Our recent results (Huang et al., 2014) have shown that the number of ERa-positive cells increases, as normal breast tissue becomes DCIS while the number of ERb-positive cells is markedly decreased during the transition. In IDC, less than 10% of tumor cells express ERb. The ERb/ERa ratio declines significantly as disease progresses from normal epithelium to DCIS and IDC. In IDC, ERa expression is negatively correlated with histological grades while most of ERb is only found in histological grade 1 (Huang et al., 2014). A recent study from a retrospective clinical trial has indicated that ERa level is inversely correlated to the grade of DCIS lesions and ERa in DCIS is a prognostic factor for tamoxifen adjuvant therapy (Allred et al., 2012). The roles of ERb in the DCIS prognosis and endocrine therapy are under investigation. 1.1.3. ERs in lobular breast cancer The incidence of invasive lobular cancer (ILC) is increasing (reviewed in Heldring et al., 2007), and the need to find better ways to treat this type of breast cancer has become more pressing. We have found that compared with ductal breast cancer; lobular breast cancer expresses high level of both estrogen receptors (Huang et al., 2014). Another marked difference between lobular and ductal cancer is the lack of proliferating cells in lobular cancer: Ki67positive cells were very abundant in ductal cancer but very rare in lobular cancer. Thus our data support the previous conclusion (Derksen et al., 2006; Vlug et al., 2014) that lobular cancer is a disease resulting from resistance to anoikis and not one of proliferation. Results from Breast Oncology Center at Dana-Farber Cancer Institute showed that the aromatase inhibitor letrozole works better than tamoxifen in the treatment of ILC in the Breast International Group (BIG) 1e98 clinical trial, while the difference of these two drugs in the treatment of IDC is very small (Metzger et al., 2012). Tamoxifen is an antagonist for ERa through EREs site, while tamoxifen in the presence of ERb is an activator at AP-1 site and stimulates proliferation (Kushner et al., 2000), the different expression levels of ERb in IDC vs. ILC (Huang et al., 2014) may account for the result from that clinical trial. 1.1.4. ERs in breast cancer microenvironment Genetic mutations within cells are not the only driving force of neoplastic transformation. Recently several studies have indicated that tumor microenvironment has a strong influence on the tumor progression, particularly tumor invasion and metastasis. Tumor microenvironment includes surrounding blood vessels, immune

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Fig. 1. Representative staining of ERa and ERb in tumor infiltrating leukocytes (TILs) from 164 female breast cancer specimens. (Scale bar ¼ 50 mm.) a and c were stained with antiERa antibody (Dako, clone: 1D5); b and d were stained with anti-ERb antibody (ERb 503 IgY). a and b were from one patient sample and c and d were from another patient sample. Detailed information about the cancer samples and immunohistochemistry method can be found in our recent publication (Huang et al., 2014).

cells, fibroblasts, other cells, signaling molecules, and the extracellular matrix (ECM). Tumor infiltrating leucocytes (TILs) are the most studied component of the cells in the tumor microenvironment and they express ERs. Recent studies have shown that immune cells can regulate cancer progression (DeNardo and Coussens, 2007; Fridman et al., 2012). Estrogen and its receptors are known to be involved in the function and regulation of immunity and inflammation (Cunningham and Gilkeson, 2011). At present, the expression patterns of ERa and ERb in immune cells in breast cancer have not been fully investigated. In our recent study using a large set of surgical excision specimens, we investigated expression of ERs in the immune cells in each patient sample. In these 188 samples, there were 164 samples with appreciable amount of TILs. In these 164 samples, we found that about 61% of TILs express ERb, but very strikingly we observed that these infiltrating immune cells do not express ERa (Fig. 1). There are more ERb-positive TILs in samples of higher histological grade. The functions of the infiltrating immune cells are still being explored (DeNardo and Coussens, 2007; Fridman et al., 2012), but it is well known that immune cells are much more abundant in the tumor than in the normal parts of the sections. The expression of ERb in TILs raises two questions: (1) whether ERb could be a useful Table 1 ERb in tumor infiltrating leukocytes (TILs). ERb staining in TILs

Number of patients

Number of patients with ERb þ TILs (percentage)

Total patients with TILs Histological grade 1 2 3

164

100 (61%)

33 95 35

14 (42%) 60 (63%) 24 (69%)

target for immune modulation in breast cancer; (2) whether tamoxifen has a beneficial or negative effect on the anti-tumor functions of TILs. Tamoxifen targets both ERa and ERb but in the presence of ERb tamoxifen is an estrogen agonist at AP-1, SP1 and NF-kB sites. Thus one of the benefits of tamoxifen use in treatment of breast cancer may be a positive influence on immune surveillance. Since there are many types of leukocytes infiltrating in human breast cancer (Ruffell et al., 2012) and the different types of leukocytes may have different and even opposite roles in the breast cancer progression (DeNardo and Coussens, 2007; Fridman et al., 2012), the ERb-positive leukocytes need to be characterized. ERb protein also has strong expression in other types of stroma cells like fibroblasts, endothelial cells in surrounding blood vessels (unpublished finding). With the increasing acknowledgement of the role of the stroma in invasiveness of cancer, the possibility that ERb can be targeted to modify stromal activity needs to be investigated. A significant portion of genes abnormally expressed in tumor epithelial and stromal cells encode secreted proteins and receptors (Allinen et al., 2004). This finding indicates that autocrine/paracrine signaling pathway may be altered during breast carcinogenesis. 1.2. Endocrine therapy targeting ERs for breast cancer treatment Since estrogen/estrogen receptor signaling plays so important a role in normal breast development and breast carcinogenesis, the strategies for targeting ERs are of concern to clinicians, researchers, as well as the pharmaceutical industry. One of the big problems of endocrine therapy is the development of resistance. Several mechanisms are proposed to explain resistance including: decrease or loss of ER; loss of PR; upregulation of HER2; and acquired dependence on ER antagonists (Giuliano et al., 2011; Musgrove and Sutherland, 2009; Osborne and Schiff, 2011). One way of avoiding resistance is use of ERb-selective agonists.

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Although many pharmaceutical companies have synthesized ERbselective agonists (reviewed in Nilsson et al., 2011; Paterni et al., 2014) and these are effective in reducing proliferation of breast cancer cells, none has been tested in breast cancer patients. One of these agonists, LY500307, has been tested in men with benign prostatic hyperplasia (BPH) and is now being tested in a clinical trial for treatment of schizophrenia (http://clinicaltrials.gov/show/ NCT01874756). There is an ongoing clinical trial to investigate the effectiveness of adjuvant endocrine therapy for operable ERb positive, ERa/PR negative, Her-2 negative breast cancer (triple negative breast cancer, TNBC) patients (http://clinicaltrials.gov/show/NCT02089854). This clinical trial will use two types of adjuvant endocrine therapy drugs, toremifene (60 mg per day for premenopausal and perimenopausal patients) and anastrozole (1 mg per day for postmenopausal patients). Even though no ERb-selective ligands are involved, since all the cancers in the study are triple negative, it is thought that the main effector of toremifene will be ERb. One important use of ERb-selective agonists that could be beneficial to all breast cancer patients would be administration in combination with aromatase inhibitors. Such a combination would provide the needed deprivation of estradiol but would prevent the devastating side effects of aromatase inhibition in the form of inflammatory joints and pain (Amir et al., 2011). Conclusion and future direction Although the knowledge of the presence of ERb has added another layer of complexity to our understanding of estrogen signaling, it has also helped us to understand some of the mysteries of estrogen action. Many new components of the estrogen signaling pathways have been discovered recently. These include: coactivators and co-repressors (Johnson and O’Malley, 2012); novel endogenous ligands such as 27-hydroxycholesterol (Nelson et al., 2013); the importance of estrogen metabolism in the breast in terminating the action of estrogen (Purohit and Foster, 2012); the role of phosphorylation of the receptor in ligand-independent activation (Yuan et al., 2014); the role of the stromal compartment in the progression of cancer (Paulsson and Micke, 2014); identification of mammary tumor initiating stem cells (Chao et al., 2014). Mammary stem cells are thought to be the cellular targets of transforming events, but we still do not know how these cells respond to estrogen. This is partly because there is no consensus as to whether or not mammary stem cells express ERs (Asselin-Labat et al., 2006). Different ligand-binding affinities and different cofactors for ERa vs. ERb allow pharmaceutical companies to synthesize ER-selective agonists (Nilsson et al., 2011). Posttranslational modification (PTM) provides another layer of regulation of ERs, and the PTM of ERa has long been indicated to play an important role in breast carcinogenesis (see review: Le Romancer et al., 2011). The ERb protein can also be posttranslational modified by phosphorylation (Yuan et al., 2014). This study showed that the level of phosphorylated Y36-specific ERb was strongly associated with both disease-free and overall survival in patients with stage II and III disease, which provides another method to target ERb in breast cancer. What is needed now is the insight to translate these discoveries into clinically useful interventions in order to better treat breast cancer patients. Acknowledgements This study was supported by grants from the Swedish Cancer Society (H2 416 233), the Robert A. Welch Foundation (Grant E0004), and the Emerging Technology Fund of Texas under Agreement 300-9-1958.

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References Allinen, M., Beroukhim, R., Cai, L., Brennan, C., Lahti-Domenici, J., Huang, H., et al., 2004. Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell 6, 17e32. Allred, D.C., Anderson, S.J., Paik, S., Wickerham, D.L., Nagtegaal, I.D., Swain, S.M., et al., 2012. Adjuvant tamoxifen reduces subsequent breast cancer in women with estrogen receptor-positive ductal carcinoma in situ: a study based on NSABP protocol B-24. J. Clin. Oncol 30, 1268e1273. Amir, E., Seruga, B., Niraula, S., Carlsson, L., Ocana, A., 2011. Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis. J. Natl. Cancer Inst 103, 1299e1309. Asselin-Labat, M.L., Shackleton, M., Stingl, J., Vaillant, F., Forrest, N.C., Eaves, C.J., et al., 2006. Steroid hormone receptor status of mouse mammary stem cells. J. Natl Cancer Inst 98 (14), 1011e1014. Bozkurt, K.K., Kapucuoglu, N., 2012. Investigation of immunohistochemical ERalpha, ERbeta and ERbetacx expressions in normal and neoplastic breast tissues. Pathol. Res. Pract 208, 133e139. Brisken, C., O’Malley, B., 2010. Hormone action in the mammary gland. Cold Spring Harb. Perspect. Biol 2, a003178. Burns, K.A., Korach, K.S., 2012. Estrogen receptors and human disease: an update. Arch. Toxicol 86, 1491e1504. Burstein, H.J., Polyak, K., Wong, J.S., Lester, S.C., Kaelin, C.M., 2004. Ductal carcinoma in situ of the breast. N. Engl. J. Med 350, 1430e1441. Chao, C.H., Chang, C.C., Wu, M.J., Ko, H.W., Wang, D., Hung, M.C., et al., 2014. MicroRNA-205 signaling regulates mammary stem cell fate and tumorigenesis. J. Clin. Invest 124, 3093e3106. Cheng, G., Butler, R., Warner, M., Gustafsson, J.A., Wilczek, B., Landgren, B.M., 2013. Effects of short-term estradiol and norethindrone acetate treatment on the breasts of normal postmenopausal women. Menopause 20, 496e503. Cunningham, M., Gilkeson, G., 2011. Estrogen receptors in immunity and autoimmunity. Clin. Rev. Allergy Immunol 40, 66e73. DeNardo, D.G., Coussens, L.M., 2007. Inflammation and breast cancer. Balancing immune response: crosstalk between adaptive and innate immune cells during breast cancer progression. Breast Cancer Res 9, 212. Derksen, P.W., Liu, X., Saridin, F., van der Gulden, H., Zevenhoven, J., Evers, B., et al., 2006. Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis. Cancer Cell 10, 437e449. Esslimani-Sahla, M., Simony-Lafontaine, J., Kramar, A., Lavaill, R., Mollevi, C., Warner, M., et al., 2004. Estrogen receptor beta (ER beta) level but not its ER beta cx variant helps to predict tamoxifen resistance in breast cancer. Clin. Cancer Res 10, 5769e5776. Fridman, W.H., Pages, F., Sautes-Fridman, C., Galon, J., 2012. The immune contexture in human tumours: impact on clinical outcome. Nat. Rev. Cancer 12, 298e306. Fuqua, S.A., Schiff, R., Parra, I., Moore, J.T., Mohsin, S.K., Osborne, C.K., et al., 2003. Estrogen receptor beta protein in human breast cancer: correlation with clinical tumor parameters. Cancer Res 63, 2434e2439. Giuliano, M., Schifp, R., Osborne, C.K., Trivedi, M.V., 2011. Biological mechanisms and clinical implications of endocrine resistance in breast cancer. Breast 20 (Suppl. 3), S42eS49. n, P., et al., Gruvberger-Saal, S.K., Bendahl, P.O., Saal, L.H., Laakso, M., Hegardt, C., Ede 2007. Estrogen receptor b expression is associated with tamoxifen response in ERa-negative breast carcinoma. Clin. Cancer Res 13, 1987e1994. Heldring, N., Pike, A., Andersson, S., Matthews, J., Cheng, G., Hartman, J., et al., 2007. Estrogen receptors: how do they signal and what are their targets. Physiol. Rev 87, 905e931. Herynk, M.H., Fuqua, S.A., 2007. Estrogen receptors in resistance to hormone therapy. Adv. Exp. Med. Biol 608, 130e143. Huang, B., Omoto, Y., Iwase, H., Yamashita, H., Toyama, T., Coombes, R.C., et al., 2014. Differential expression of estrogen receptor alpha, beta1, and beta2 in lobular and ductal breast cancer. Proc. Natl. Acad. Sci. U.S.A. 111, 1933e1938. Jarvinen, T.A., Pelto-Huikko, M., Holli, K., Isola, J., 2000. Estrogen receptor b Is coexpressed with ERa and PR and associated with nodal status, grade, and proliferation rate in breast cancer. Am. J. Pathol 156, 29e35. Johnson, A.B., O’Malley, B.W., 2012. Steroid receptor coactivators 1, 2, and 3: critical regulators of nuclear receptor activity and steroid receptor modulator (SRM)based cancer therapy. Mol. Cell. Endocrinol 348, 430e439. Korhonen, T., Huhtala, H., Holli, K., 2004. A comparison of the biological and clinical features of invasive lobular and ductal carcinomas of the breast. Breast Cancer Res. Treat 85 (1), 23e29. Kushner, P.J., Agard, D.A., Greene, G.L., Scanlan, T.S., Shiau, A.K., Uht, R.M., et al., 2000. Estrogen receptor pathways to AP-1. J. Steroid Biochem. Mol. Biol 74, 311e317. Le Romancer, M., Poulard, C., Cohen, P., Sentis, S., Renoir, J.M., Corbo, L., 2011. Cracking the estrogen receptor’s posttranslational code in breast tumors. Endocr. Rev 32, 597e622. Leygue, E., Murphy, L.C., 2013. A bi-faceted role of estrogen receptor beta in breast cancer. Endocr. Relat. Cancer 20, R127eR139. Li, S., Han, B., Liu, G., Ouellet, J., Labrie, F., Pelletier, G., 2010. Immunocytochemical localization of sex steroid hormone receptors in normal human mammary gland. J. Histochem. Cytochem 58, 509e515. Metzger, A.G.-H., Mallon, E., Viale, G., Winer, E., Thürlimann, B., Gelber, R.D., et al., 2012. Relative effectiveness of letrozole compared with tamoxifen for patients

244

B. Huang et al. / Molecular and Cellular Endocrinology 418 (2015) 240e244

with lobular carcinoma in the BIG 1-98 trial. Cancer Res 72 (24 Suppl.). Abstract nr S1-1. Miller, W.R., Anderson, T.J., Dixon, J.M., Saunders, P.T.K., 2006. Oestrogen receptor b and neoadjuvant therapy with tamoxifen: prediction of response and effects of treatment. Br. J. Cancer 94, 1333e1338. Miyoshi, Y., Taguchi, T., Gustafsson, J.A., Noguchi, S., 2001. Clinicopathological characteristics of estrogen receptor-beta-positive human breast cancers. Jpn. J. Cancer Res 92, 1057e1061. Murphy, L.C., Leygue, E., 2012. The role of estrogen receptor-beta in breast cancer. Semin. Reprod. Med 30, 5e13. Musgrove, E.A., Sutherland, R.L., 2009. Biological determinants of endocrine resistance in breast cancer. Nat. Rev. Cancer 9, 631e643. Nelson, E.R., Wardell, S.E., Jasper, J.S., Park, S., Suchindran, S., Howe, M.K., et al., 2013. 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. Science 342, 1094e1098. Nilsson, S., Koehler, K.F., Gustafsson, J.A., 2011. Development of subtype-selective oestrogen receptor-based therapeutics. Nat. Rev. Drug Discov 10, 778e792. Omoto, Y., Kobayashi, S., Inoue, S., Ogawa, S., Toyama, T., Yamashita, H., et al., 2002. Evaluation of oestrogen receptor b wild-type and variant protein expression, and relationship with clinicopathological factors in breast cancers. Eur. J. Cancer 38, 380e386. O’Neill, P.A., Davies, M.P.A., Shaaban, A.M., Innes, H., Torevell, A., Sibson, D.R., et al., 2004. Wild-type oestrogen receptor beta (ERb1) mRNA and protein expression in Tamoxifen-treated post-menopausal breast cancers. Br. J. Cancer 91, 1694e1702. Osborne, C.K., Schiff, R., 2011. Mechanisms of endocrine resistance in breast cancer. Annu. Rev. Med 62, 233e247. Paterni, I., Granchi, C., Katzenellenbogen, J.A., Minutolo, F., 2014. Estrogen receptors alpha (ERalpha) and beta (ERbeta): Subtype-selective ligands and clinical potential. Steroids. http://dx.doi.org/10.1016/j.steroids.2014.06.012. Paulsson, J., Micke, P., 2014. Prognostic relevance of cancer-associated fibroblasts in human cancer. Semin. Cancer Biol 25, 61e68. Polyak, K., 2007. Breast cancer: origins and evolution. J. Clin. Invest 117, 3155e3163. Purohit, A., Foster, P.A., 2012. Steroid sulfatase inhibitors for estrogen- and androgen-dependent cancers. J. Endocrinol 212, 99e110. Roger, P., Sahla, M.E., Makela, S., Gustafsson, J.A., Baldet, P., Rochefort, H., 2001. Decreased expression of estrogen receptor beta protein in proliferative preinvasive mammary tumors. Cancer Res 61, 2537e2541. Ruffell, B., Au, A., Rugo, H.S., Esserman, L.J., Hwang, E.S., Coussens, L.M., 2012. Leukocyte composition of human breast cancer. Proc. Natl. Acad. Sci. U.S.A. 109,

2796e2801. Saunders, P.T., Millar, M.R., Williams, K., Macpherson, S., Bayne, C., O’Sullivan, C., et al., 2002. Expression of oestrogen receptor beta (ERbeta1) protein in human breast cancer biopsies. Br. J. Cancer 86, 250e256. Sgroi, D.C., 2010. Preinvasive breast cancer. Annu. Rev. Pathol 5, 193e221. Shaaban, A.M., O’Neill, P.A., Davies, M.P., Sibson, R., West, C.R., Smith, P.H., et al., 2003. Declining estrogen receptor-beta expression defines malignant progression of human breast neoplasia. Am. J. Surg. Pathol 27, 1502e1512. Shaw, J.A., Udokang, K., Mosquera, J.M., Chauhan, H., Jones, J.L., Walker, R.A., 2002. Oestrogen receptors alpha and beta differ in normal human breast and breast carcinomas. J. Pathol 198, 450e457. Skliris, G.P., Carder, P.J., Lansdown, M.R.J., Speirs, V., 2001. Immunohistochemical detection of ERb in breast cancer: towards more detailed receptor profiling? Br. J. Cancer 84, 1095e1098. Skliris, G.P., Munot, K., Bell, S.M., Carder, P.J., Lane, S., Horgan, K., et al., 2003. Reduced expression of oestrogen receptor beta in invasive breast cancer and its re-expression using DNA methyl transferase inhibitors in a cell line model. J. Pathol 201, 213e220. Skliris, G.P., Leygue, E., Curtis-Snell, L., Watson, P.H., Murphy, L.C., 2006. Expression of oestrogen receptor-beta in oestrogen receptor-alpha negative human breast tumours. Br. J. Cancer 95, 616e626. Speirs, V., Parkes, A.T., Kerin, M.J., Walton, D.S., Carleton, P.J., Fox, J.N., et al., 1999. Coexpression of estrogen receptor and b: poor prognostic factors in human breast cancer. Cancer Res 59, 525e528. Sugiura, H., Toyama, T., Hara, Y., Zhang, Z., Kobayashi, S., Fujii, Y., et al., 2007. Expression of estrogen receptor b wild-type and its variant ERbcx/b2 is correlated with better prognosis in breast cancer. Jpn. J. Clin. Oncol 37, 820e828. Thomas, C., Gustafsson, J.A., 2011. The different roles of ER subtypes in cancer biology and therapy. Nat. Rev. Cancer 11, 597e608. Vlug, E., Ercan, C., van der Wall, E., van Diest, P.J., Derksen, P.W., 2014. Lobular breast cancer: pathology, biology, and options for clinical intervention. Arch. Immunol. Ther. Exp. (Warsz) 62, 7e21. Warner, M., Gustafsson, J.A., 2010. The role of estrogen receptor beta (ERbeta) in malignant diseasesea new potential target for antiproliferative drugs in prevention and treatment of cancer. Biochem. Biophys. Res. Commun 396, 63e66. Wellings, S.R., Jensen, H.M., 1973. On the origin and progression of ductal carcinoma in the human breast. J. Natl Cancer Inst 50, 1111e1118. Yuan, B., Cheng, L., Chiang, H.C., Xu, X., Han, Y., Su, H., et al., 2014. A phosphotyrosine switch determines the antitumor activity of ERbeta. J. Clin. Invest 124, 3378e3390.

Estrogen receptors in breast carcinogenesis and endocrine therapy.

Excessive exposure to estrogen has long been associated with an increased risk for developing breast cancer and anti-estrogen therapy is the gold stan...
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