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Steroid Hormone Receptors As Prognostic Markers in Breast Cancer

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Steroid Hormone Receptors As Prognostic Markers in Breast Cancer Dominican Scholar Natural Sciences and Mathematics | Department of Natural Sciences and Faculty Scholarship Mathematics 1-1-2017 Steroid hormone receptors as prognostic markers in breast cancer. Maggie Louie Department of Natural Sciences and Mathematics, Dominican University of California, [email protected] Mary B. Sevigny Department of Natural Sciences and Mathematics, Dominican University of California, [email protected] Survey: Let us know how this paper benefits you. Recommended Citation Louie, Maggie and Sevigny, Mary B., "Steroid hormone receptors as prognostic markers in breast cancer." (2017). Natural Sciences and Mathematics | Faculty Scholarship. 40. https://scholar.dominican.edu/natural-sciences-and-mathematics-faculty-scholarship/40 This Article is brought to you for free and open access by the Department of Natural Sciences and Mathematics at Dominican Scholar. It has been accepted for inclusion in Natural Sciences and Mathematics | Faculty Scholarship by an authorized administrator of Dominican Scholar. For more information, please contact [email protected]. Am J Cancer Res 2017;7(8):1617-1636 www.ajcr.us /ISSN:2156-6976/ajcr0060310 Review Article Steroid hormone receptors as prognostic markers in breast cancer Maggie C Louie*, Mary B Sevigny* Department of Natural Sciences and Mathematics, Dominican University of California, 50 Acacia Avenue, San Rafael, CA 94901, USA. *Equal contributors. Received June 26, 2017; Accepted July 5, 2017; Epub August 1, 2017; Published August 15, 2017 Abstract: Despite the existence of many promising anti-cancer therapies, not all breast cancers are equally treat- able, due partly to the fact that focus has been primarily on a few select breast cancer biomarkers- notably ERα, PR and HER2. In cases like triple negative breast cancer (ERα-, PR-, and HER2-), there is a complete lack of available biomarkers for prognosis and therapeutic purposes. The goal of this review is to determine if other steroid recep- tors, like ERβ and AR, could play a prognostic and/or therapeutic role. Data from various in vitro, in vivo, and clinical breast cancer studies were examined to analyze the presence and function of ERβ, PR, and AR in the presence and absence of ERα. Additionally, we focused on studies that examined how expression of the various steroid receptor isoforms affects breast cancer progression. Our findings suggest that while we have a solid understanding of how these receptors work individually, how they interact and behave in the presence and absence of other receptors requires further research. Furthermore, there is an incomplete understanding of how the various steroid receptor isoforms interact and impact receptor function and breast cancer progression, partly due to the difficulty in detect- ing all the various isoforms. More large-scale clinical studies must be made to analyze systematically the expression of steroid hormone receptors and their respective isoforms in breast cancer patients in order to determine how these receptors interact with each other and in turn affect cancer progression. Keywords: Breast cancer, steroid hormone receptors, prognostic markers, estrogen, progesterone, androgen Introduction mine their role and utility as prognostic markers and therapeutic targets. Though both estrogen and progesterone recep- tors are commonly used as prognostic markers Steroid receptors: an overview for breast cancer, current endocrine therapy primarily targets the estrogen receptor, ERα. The steroid hormone receptor subfamily, which Unfortunately, for about 10-15% of breast can- includes estrogen receptor (ER), progesterone cer patients [1-3]- like those diagnosed with receptor (PR), androgen receptor (AR), and glu- triple negative breast cancer, defined as breast cocorticoid receptor (GR), is part of the larger tumors lacking the expression of estrogen superfamily of nuclear hormone receptors [4]. receptor alpha (ERα), progesterone receptor The members of this superfamily function as (PR) and human epidermal growth factor recep- ligand-gated transcription factors that modu- tor type 2 (HER2), ERα-/PR-/HER2- - the estab- late the expression of genes [5]. While unbound lished endocrine therapies are ineffective, steroid receptors are typically located in the highlighting an urgent need for additional thera- cytosol, ligand binding induces receptor dimer- peutic targets in breast cancer. Therefore, the ization and conformational changes which in goal of the following review is to examine the turn exposes the nuclear localization signal, role of the steroid hormone receptors- ERα, allowing translocation into the nucleus [6]. ERβ, PR, and androgen receptor (AR)- in the Once inside the nucleus, the receptor dimer progression of breast cancer in order to deter- recognizes and binds specific DNA sequences Steroid receptors and breast cancer Estrogen receptor The estrogen receptor (ER) was identified in the 1950s by Dr. Elwood V. Jensen as reviewed in [14, 15]. Even- tually, it was determined that three forms of ER exist- ERα, ERβ, and GPR-30 [16-19]. All three ERs are encoded by different genes located on different chromosomes [20]. ERα is encoded by the gene ESR1 located on chromo- some 6; ERβ is encoded by Figure 1. Comparing the functional domains of nuclear hormone receptors. NTD, N-terminal A/B hypervariable domain; DBD, DNA binding domain; H, gene ESR2 on chromosome hinge region; LBD, ligand binding domain. Adapted from [196]. 14; and GPR-30 is encoded by the GPER gene on chro- mosome 7. While ERα and that in turn results in enhancing or silencing the ERβ are nuclear hormone receptors, GPR-30 is transcription of specific target genes regulated not a member of the steroid receptor family but by the receptor [7, 8]. is instead a G-protein coupled receptor that has been shown to bind and respond to estro- As depicted in Figure 1, nuclear hormone gen [21-23]. Therefore, since our interest is in receptors share common functional domains, the role of steroid hormone receptors in breast such as a DNA binding domain (DBD), a ligand cancer, GPR-30 will not be discussed further in binding domain (LBD), and two transactivation this review. domains (AF-1 and AF-2) [9-12]. DBDs contain two zinc finger motifs that allow them to recog- Although ERα and ERβ are both expressed in nize and bind to specific DNA sequences- often breast tissue and bind to estrogen with similar referred to as hormone response elements affinities [24], studies have shown that only (HREs)- within the promoter and/or enhancer ERα is necessary for normal mammary gland regions to regulate transcription. Different ste- development [25, 26] leading researchers to roid hormone receptors bind to different re- question the function of ERβ in normal breast sponse elements, thus allowing the receptors tissue. Multiple studies have also reported that to regulate subsets of genes that are necessary ERβ expression actually represses ERα expres- to elicit a physiological response. The LBD is sion and function [27, 28]. In addition to the involved in the binding of specific hormones, breast, both nuclear receptors are expressed in which induces dimerization and nuclear trans- many other tissues within the human body, location [9-12]. The two transactivation doma- including the endometrium, ovary, testes, cere- ins, AF-1 and AF-2, are important for modulat- bral cortex, myocardium, and thyroid [29-32]. ing transcription of the target genes. AF-2 is However, their expression patterns do differ in located within the LBD and is involved in ligand- certain tissues- for example, ERα is the sole dependent transactivation, while AF-1 is found estrogen receptor expressed in the hippocam- in the N-terminal A/B hypervariable domain pus, and only ERβ is found in prostate tissue (NTD) and is responsible for ligand-indepen- [32]. dent transcriptional activation and mediates protein-protein interaction with other trans- In addition to full length ERα (as shown in cription factors [13]. AF-1 is also responsive Figure 1), there are 2 truncated splice variants to phosphorylation by kinases that are activat- of ERα- 46 kDa estrogen receptor (ER46) [33] ed in various signaling pathways, including and 36 kDa estrogen receptor (ER36) [34, 35]. the epidermal growth factor receptor (EGFR) Some of the full length ERα (ER66) along with pathway. ER36 and ER46 [36] associate with the plasma 1618 Am J Cancer Res 2017;7(8):1617-1636 Steroid receptors and breast cancer membrane and are referred to as mERs due to scription activation properties when bound to their ability to translocate to the plasma mem- progesterone [53, 54]. According to Richer et brane through palmitoylation and caveolin-1 al., approximately 27% of PR-regulated genes association, which in turn allows for rapid estro- are controlled by both PR isoforms. However, gen receptor signaling. ER46 does not have an this study also indicated that PR-B alone con- AF-1 transactivation domain, which suggests trols the majority of the PR-regulated genes in that ER46 does not mediate any nuclear func- comparison to PR-A alone (69% versus 4%) [55] tions. ER36 lacks both AF-1 and AF-2 transacti- which may be in part due to PR-B being intrinsi- vation domains, and part of the ligand binding cally a stronger transcriptional activator than domain is replaced by a 27 amino acid PR-A. In fact, PR-A has been reported to func- sequence in the C terminus [34]. ER36 has tion as a transcriptional repressor under cer- been shown to mediate estrogen stimulation tain cellular conditions [56]. Curiously however, via mitogen-activated protein kinase (MAPK) it is PR-A- not PR-B- that is more frequently pathway [35]. over-expressed in breast cancer [57]. Some studies have even indicated that it is not so As with ERα, ERβ also exists as several iso- much the expression of either isoform but rath- forms- ERβ1 (Figure 1), ERβ1 “short form”, er the ratio of the two isoforms that are impor- ERβ2/cx, ERβ3, ERβ4, and ERβ5 [37-40]. Most tant in breast cancer development.
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