From Seminars in Reproductive Medicine
The Role of Estrogen Receptor-Î² in Breast Cancer
Leigh C. Murphy, Ph.D.; Etienne Leygue, Ph.D.
Posted: 02/09/2012; Semin Reprod Med. 2012;30(1):5-13. © 2012 Thieme Medical Publishers
Abstract and Introduction
The discovery of a second estrogen receptor (ER), ERÎ², has led to a reevaluation of estrogen action. The widespread expression of ERÎ²-like proteins in normal and neoplastic mammary tissues suggests a role of ERÎ² in the breast. Little progress has been made in elucidating this role or roles, but the presence of two ERs and variant isoforms in breast cancers presents challenges and opportunities to tease out complexities in understanding the estrogen signaling pathway in breast tissues. Identification of two groups of ERÎ²-expressing tumors in vivo, and the possibility of differential function, has already raised expectations that targeting ERÎ² may offer new treatment options for breast cancer patients where previously only aggressive chemotherapies were available. This supports continued efforts to understand the nature and function of ERÎ² in breast cancer, but it also suggests that ER status may need to be redefined to include an assessment of ERÎ² isoforms in addition to ERÎ±.
The estrogen receptor (ER) is central to the biology of most human breast cancer. As such, ER has been and continues to be the target for the treatment and prevention of breast cancer. However, the ER is no longer a stand-alone molecule associated with a linear signaling pathway. ER signaling is now known to be remarkably complex and multifaceted. In particular, the discovery of a second ER, called ERÎ², has been instrumental in a reevaluation of estrogen action in all tissues, either normal or neoplastic. Gene knockout studies clearly identify ERÎ± expression as essential for normal mammary gland development. ERÎ± today remains the primary target for endocrine therapies in breast cancer. As such, its levels are measured to determine the ER status of primary tumors and to predict the likelihood of patients responding positively to tamoxifen treatment, for example. Such data, in addition to >30 years of discovery and clinical experimentation, have established a central role of ERÎ± in both normal and neoplastic mammary growth. In contrast, although 15 years have passed since the discovery of ERÎ², the significance of its expression and its potential roles in normal mammary development, breast tumorigenesis, or tumor progression remain controversial and unclear. This article reviews the current research focused on elucidating the role of ERÎ² in breast cancer.
Estrogen Receptor-Î² and Normal Mammary Gland
The expression of ERÎ² in the normal mammary gland of both mouse and human has been investigated. In both cases ERÎ² is widely expressed in multiple normal mammary gland cellular compartments, including luminal and myoepithelium. This is in stark contrast to ERÎ±, where only infrequent luminal epithelial staining is reported. Similarly, if the ERÎ± knockout mouse models show no mammary gland development, only small effects on mammary gland differentiation and overall none on its function are reported for the ERÎ² knockout.[3,4] It should be noted, however, that differences between ERÎ² knockout models and different laboratories have been observed.[3,5,6]
Therefore, somewhat paradoxically, despite ERÎ² being the most frequently expressed ER in the normal mammary gland, it does not appear to be the most important with respect to normal development and function, at least as determined from mouse gene ablation studies.
Estrogen Receptor-Î² and Breast Cancer
The expression of ERÎ² in human breast tumors was first reported in 1997 when ERÎ² RNAs were detected in multiple human breast cancer biopsy samples.[7,8] Demonstration of ERÎ²-like protein expression in breast tumors by Western blotting and by immunohistochemistry followed quickly thereafter.[9,10] These reports established the platform for many subsequent studies in which clinical samples were investigated for ERÎ² expression. Relationships between this expression and clinicopathological parameters and patient outcome were investigated to obtain insight into the possible function of ERÎ² in breast cancer. Although results that have emerged from the latter type approach together with results generated from laboratory studies have provided some significant insights, several important complexities associated with measuring ERÎ² expression and establishing its exact functions have also emerged. These complexities are likely to have an impact on our understanding of the overall roles that ERÎ² plays in breast cancer. These complexities include the presence of multiple variant isoforms of ERÎ², consideration of differential functions when ERÎ² is expressed alone versus those when it is coexpressed with ERÎ±, and methods of determining ERÎ² expression.[11-15]
Estrogen Receptor-Î² Variants
Fig. 1 illustrates schematically the similarities and differences in the structure of ERÎ²1 and ERÎ±. Also illustrated are two C-terminally truncated ERÎ² variants, ERÎ² 2/cx and ERÎ² 5, and an N-terminally truncated short form of ERÎ² 1. Most of the variant isoforms have been detected at the RNA level, even though in some cases, the predicted protein has also been detected in breast tumors.[16-19] Most of these isoforms are generated by alternative splicing mechanisms. In contrast, an N-terminally truncated short form of ERÎ² 1 may be generated posttranslationally by proteolysis. Other posttranslational modifications have been reported, including detection of a phosphorylated form of ERÎ² in multiple human breast tumors.[22,23]
Schematic representation of human estrogen receptor (ER)Î± (hERÎ±) and some ER-Î² (hERÎ²) isoform proteins. Human ERÎ² 1 (hERÎ² 1) is the full-length ligand-binding form, and ERÎ² 2 (hERÎ² 2/cx) and ERÎ² 5 (hERÎ² 5) are two common C-terminally truncated variants unable to bind ligands.
A common observation is that ERÎ² expression is decreased in cancer compared with the equivalent normal tissue.[24-27] Mechanisms potentially associated with this downregulation of ERÎ² expression include increased methylation of the ERÎ² promoter, microRNAs, and other posttranscriptional regulatory mechanisms.[28-30] As a direct result of these overall low ERÎ² levels in breast cancer cells, there are few, if any, cell line models where reliable ERÎ² expression has been demonstrated. Most of the models developed to study ERÎ² protein function have therefore been generated using either upregulated transient, constitutive stable, or inducible stable expression of ERÎ²-like proteins in cultured cell lines and xenografts from these cell lines.[31-37] A common conclusion has been that ERÎ² 1, the full-length ligand binding isoform (ERÎ² 1), is antiproliferative and proapoptotic.[32,34,38] However, in stark contrast to the latter conclusions are models in which ERÎ² 1 overexpression is growth stimulatory or has no effect on proliferation and/or cell death.[36,37,39] Furthermore, there are published data reporting correlations of ERÎ² expression with both pro- and antiproliferative activity in normal mammary cells.[40,41] The reasons for such differences remain unknown, even though current data indicate that differences in species and/or cell background, in particular p53 status, type of ERÎ², unknown clonal selection variables, and level of expression, may influence ERÎ²’s effect on proliferation. It is unclear whether the increased expression of ERÎ² 1 in experimental systems is relevant to the levels of ERÎ² seen in tumors and/or normal tissues in vivo, especially because ERÎ² is often downregulated in tumors compared with normal tissues.[24-26]
It is interesting that the only models showing an association of overexpression of ERÎ² 1 with increased proliferation, invasiveness, and metastasis is when it has been introduced into a breast cancer cell line that is ERÎ± negative.[36,37] This may be highly relevant when interpreting the differences seen in vivo when the expression of ERÎ² 1 alone in human breast tumors is compared with its coexpression with ERÎ±.[11,12,43]
Most studies of ERÎ² function and mechanisms of action have focused on ERÎ² 1, and considerably less is known about putative roles played by ERÎ² variants. The most studied variant is the ERÎ² 2/cx. Here again, different activities in apparently similar model systems have been observed using overexpression approaches. Generally, the C-terminally truncated ERÎ² variants such as ERÎ² 2/cx and ERÎ² 5 are thought to have little activity of their own. They can, however, influence the activity of either ERÎ² 1 and ERÎ± when coexpressed, either inhibiting or enhancing these two ligand binding forms of ERs.[17,44-46] Using stable overexpression of ERÎ² 2/cx in MCF7 cells, inhibition of cell cycling and colony growth in soft agar were reported. Part of the mechanism involved was thought to be inhibition of ERÎ± activity due to ERÎ±/ERÎ² 2/cx heterodimer formation, resulting in a proteasome-dependent degradation of ERÎ±. In contrast, this was not seen in another model of overexpression of ERÎ² 2/cx in MCF7 cells despite decreased expression of ERÎ± downstream targets such as the progesterone receptor.
More recently, the existence of an N-terminally truncated shorter form of ERÎ² 1 was reported that may be functionally distinct from the longer form of ERÎ² 1.[21,48] Other limited experimental studies can be interpreted to suggest that the long and short forms of ERÎ² 1 may have differential effects on inflammatory/immune activities. Given the anti-inflammatory activities of ERÎ² 1, the relative expression of the long and short forms of ERÎ² 1 might have functional implications in breast cancer.[50-52]
Expression of Estrogen Receptor-Î² in Breast Tumors in vivo
Consistently decreased expression of ERÎ² 1 protein levels from normal to invasive breast cancer has been described in several studies.[24,53] In contrast, ERÎ± expression is increased during mammary tumorigenesis, and ERÎ² 2/cx expression has also be shown to be increased in breast tumors compared with normal breast tissue.[54,55] Overall, there appears to be a marked alteration of the relative expression of not only ERÎ² 1 and ERÎ± but also the relative expression of ERÎ² isoforms during breast tumorigenesis.[56,57] This is consistent with the known alteration of estrogen signaling that occurs during breast cancer development and suggests that the altered levels of ERÎ² isoforms could also, in part, underlie this altered estrogen signaling. On a side note, although originally thought to possibly result from so-called hiccups of the splicing machinery, alternative splicing events have now been shown to be highly controlled and to introduce a new layer of complexity in the regulation of gene expression.[58-61] Alternative splicing as such is suspected to participate in various pathologies including skin diseases, neurodegeneration, and cancer.[62-66] One might speculate that modifications of the splicing events controlling the respective proportion of ERÎ² isoforms, through the resulting alterations of ER signaling and hence response to estrogen, contribute not only to breast tumorigenesis but also to resistance to specific endocrine therapies.
Despite ERÎ² 1 downregulation in invasive breast cancer, a significant number of invasive breast cancers still express ERÎ² 1.[11,15] Several studies have now been published in which expression of ERÎ²-like proteins in tumors was correlated with known histopathological and clinical parameters to gain further insight into the potential role played by these proteins in breast cancer.
Multiple studies along these lines have now been published. However, they led to varied and often contradictory results. This may, in part, be due to how ERÎ² expression was determined (RNA or protein), which antibody was used to determine protein expression, definitions of ERÎ² positivity and negativity, and a lack of appreciation that when considering ERÎ² expression, there are clearly two groups to take into account: one in which ERÎ² is coexpressed with ERÎ± and the second where ERÎ² is expressed alone.
Because ERÎ² can, in addition to actual tumor cells, also be expressed in other cell types, such as infiltrating lymphocytes, other immune cells, and fat and vascular cells that make up a heterogeneous breast tumor in vivo, studies investigating globally extracted RNAs may be difficult to interpret. Studies using microdissected invasive cells can overcome this issue. Approaches where ERÎ² expression is assessed taking into account the cellular location within a tumor sample are likely to be the most informative, as are those that accurately determine the exact nature of the ERÎ² isoforms expressed. Therefore, immunohistochemical studies using well-characterized antibodies to specific ERÎ² epitopes located in the N-terminus and therefore detecting “total” ERÎ²-like (i.e., the sum of ERÎ² 1 long and short, ERÎ² 2/cx, ER Î² 5, etc.) proteins or those using antibodies specific for a given ERÎ² isoform (e.g., ERÎ² 1 only) are the focus of the following discussion.
Since last reviewed in 2008, several other studies have been published. As such, there are at least 23 studies now reporting detection of ERÎ²-like proteins in tumors from >3000 human breast cancer cases with correlations to clinical outcome ( Table 1 ).[68,69] Most but not all of these studies find associations of higher levels of ERÎ²-like proteins with better clinical outcome, often in patients who have been treated with tamoxifen therapy. In many of these cases ERÎ² 1 was determined using specific antibodies to the C-terminal region of this receptor. However, similar conclusions were made using antibodies to an N-terminal epitope that would recognize total ERÎ²-like proteins, and some studies have used antibodies to the ERÎ² 2/cx C-terminal region with similar conclusions. Of the seven studies in which both ERÎ² 1 and ERÎ² 2/cx were compared, two[12,71] found no association of either isoform with clinical outcome, one found that high levels of ERÎ² 2/cx and ERÎ² 1 were associated with better clinical outcome, one found that high levels of ERÎ² 2/cx but not ERÎ² 1 were associated with better clinical outcome, and three[19,68,73] found that high levels of ERÎ² 1 but not ERÎ² 2/cx were associated with better clinical outcome. In most cases only nuclear staining of the ERÎ² proteins was determined, although two studies determined both nuclear and cytoplasmic staining of the ERÎ² isoforms and provided evidence that subcellular localization of ERÎ² 2/cx was differentially associated with clinical outcome.[18,19] Both these latter studies identified the cytoplasmic localization of ERÎ² 2/cx as associated with poor clinical outcome. Several of the studies also suggest that the level of ERÎ² was predictive of outcome due to tamoxifen treatment.[68,69] More recently, higher levels of ERÎ² 1 were also associated with better clinical outcome in patients treated with aromatase inhibitors.[74,75]
Further insight into the possible reasons for the contradictory results associated with ERÎ² expression and its association with clinical outcome, in particular in patients treated with tamoxifen, comes with a recent prospective study in which ERÎ² 1 expression was compared across four intrinsic molecular subtypes, previously classified by expression profiling.[76,77] Interestingly, ERÎ² 1 expression was evenly distributed across the luminal A, luminal B, HER2, and triple negative subtypes. High levels were differentially associated with clinical outcome, however, depending on whether the patients were node positive or negative. This was most marked between the luminal A and luminal B subtypes, where high ERÎ² 1 expression was associated with good clinical outcome in luminal A node-negative but not node-positive groups. In contrast, high ERÎ² 1 expression was associated with poor clinical outcome in luminal B node-positive but not node-negative groups. Luminal A and B subtypes are generally ERÎ± positive and in previous studies would have been considered as one group (ER+) and likely be eligible for endocrine therapy. Differential representation of these two molecular subtypes plus or minus nodal involvement in previous retrospective studies could therefore have significantly affected the results deduced.
Most of the studies already cited focused on ER+(i.e., ERÎ±-positive breast cancer), so they represent ERÎ² coexpressed with ERÎ± and are often treated with endocrine therapies. So a general conclusion is that higher levels of ERÎ²-like proteins in the presence of ERÎ± in human breast cancer are associated with a better prognosis and the increased likelihood of responsiveness to endocrine therapies. These data also support the idea that ER profiling (determination of ERÎ±, ERÎ² 1, and ERÎ² 2/cx and the development of an ER isoform code) may provide a more accurate biomarker for prognosis and treatment response prediction than what is currently available.
The mechanism underlying this conclusion may be associated with the ability of several ERÎ² isoforms to heterodimerize with ERÎ± and negatively modulate ERÎ± activity.[20,45,47] Furthermore, one model of inducible ERÎ² 1 expression in ERÎ±-positive MCF7 cells reported that increased ERÎ² 1 is associated with increased sensitivity to the growth inhibitory effects of 4-hydroxy-tamoxifen, and more recently for increased sensitivity of breast cancer to endoxifen, an active metabolite of tamoxifen in vivo.[31,78] These results further support a direct mechanistic role of ERÎ² 1 in endocrine therapy sensitivity in vivo.
Despite the relatively few studies undertaken to date with a focus on ERÎ±-negative but ERÎ²-positive breast cancer, there is a generally consistent conclusion that ERÎ² 1 likely has a different role in these tumors and could be a targeted treatment option for patients who otherwise have few options except aggressive chemotherapies.[12,43,69,79] The first data supporting a differential role for ERÎ² in ERÎ±-negative breast cancer showed a positive correlation of ERÎ² 1 with markers of proliferation (Ki 67) and cell cycling (cyclin A).[12,43,79] At least in one study, the association was found for ERÎ² 1 but not ERÎ² 2/cx, supporting the idea that a selective ligand targeting was feasible. Given the often found antiproliferative and proapoptotic activities of overexpressed ERÎ² 1 in cells in culture, irrespective of the ERÎ± status, the mechanism of ERÎ²1’s positive association with proliferation is unclear at this point. It must be pointed out, however, that the nature of ERÎ² 1 in ERÎ±-negative tumors (i.e., short versus long form, any posttranslational modifications or mutated ERÎ² 1) has not been investigated.
The importance of understanding the role of ERÎ² 1 expression alone in breast cancer has been heightened with the publication of two studies where ERÎ² expression was determined by immunohistochemistry using archival pathology blocks representing ERÎ±-negative breast cancer patients who had been treated with adjuvant tamoxifen for 2 years with long-term follow-up.[68,69] Both studies reported that ERÎ² positivity was associated with significantly better survival. Because one of them measured ERÎ² 1, tamoxifen binding to ERÎ² 1 being directly involved in the mechanism mediating the treatment effect is a real and exciting possibility. As well, ERÎ² 1 expression was found to be an important prognostic marker in triple-negative breast cancer patients treated with tamoxifen in a subgroup analysis. As mentioned previously, the implications are that targeting ERÎ² 1 pathway(s) may be a treatment option for such patients who generally have few options other than aggressive chemotherapies, and some clinical trials are underway to address such a possibility, including the ANZ 1001 SORBET study coordinated by the Australian New Zealand Breast Cancer Trials Group (ANZ CTRN: 12610000506099).
Markers of Estrogen Receptor-Î² Functionality in Breast Cancer
The emerging idea that the function of ERÎ² 1 may be different in breast cancer when it is expressed alone to that when its coexpressed with ERÎ±, underscores the need to identify downstream targets of ERÎ² 1 functionality in human breast cancer. Historically, downstream markers of ERÎ± functionality such as the progesterone receptor and pS2, have proven useful clinically in more accurately predicting prognosis and responsiveness to endocrine therapies.[80,81] Therefore, reliable downstream specific markers of ERÎ² activity would be extremely valuable in elucidating roles of ERÎ² and in providing more accurate biomarkers of a functionally intact ERÎ² signaling pathway in both ERÎ±-positive and -negative tumors. In 2008, a unique ERÎ²-associated gene expression profile was described, only in ERÎ±-negative but not ERÎ±-positive breast tumors. This not only supports a differential function of ERÎ² 1 when expressed alone, but it also supports the likelihood that distinct downstream targets of ERÎ² 1 exist and are relevant to human breast cancer in vivo. A few gene expression profiling, chromatin-immunoprecipitation (ChiP)-on-chip and ChiP-seq studies have been published using ERÎ² 1 overexpressing ERÎ±-positive MCF7 breast cancer cell models to identify ERÎ² 1 regulated genes and gene networks.[32,33,82,83] This of course models ERÎ² 1 coexpression with ERÎ±, and only one study has been reported on expression profiling of the ERÎ±-negative breast cancer cell line, Hs578T, stably expressing inducible ERÎ² 1 expression. This models ERÎ² 1 expression alone in breast cancer.
These global expression and genome-wide binding site analyses are still in the early stages and as yet have not provided unique molecular signatures that have been applied to large numbers of breast cancer cases and correlated with ERÎ² expression and clinical outcome. Some general themes are emerging, however. In some cases ERÎ² has been identified to regulate genes that are part of transforming growth factor (TGF)-Î²-like signaling pathways. If this is supported by further analyses, it is possible that altered ERÎ² action during cancer progression may be mediated in part through alteration of TGF-Î²-like signaling.[27,85,86] Regulation of individual genes and gene networks associated with proliferation, the cell cycle, and apoptosis is a common feature in estrogen-treated breast cancer models of ERÎ² overexpression with ERÎ±.[32,33,87] Substantial overlap of ERÎ± and ERÎ² 1 binding sites using genome-wide binding analyses, which are enriched for estrogen response element (ERE) motifs, has also been reported. However, ERÎ± can displace ERÎ² 1 to different sites that are less enriched for ERE motifs when ERÎ± and ERÎ² 1 are coexpressed and estrogen treated.[32,82,88] Interestingly, in the only study published so far where an originally ER-negative breast cancer cell line was engineered to stably overexpress either ERÎ± or ERÎ² 1, it was concluded that each receptor mainly regulated unique gene sets. As well in this same analysis, a model of ERÎ² 2/cx expression alone was found to have no effect on either proliferation or gene expression in breast cancer cells, suggesting this variant requires coexpression with either ERÎ± or ERÎ² 1 to mediate activity. There is an obvious need to develop and analyze more models of ERÎ² 1 expression alone using both global expression profiling and genome-wide binding analyses, and to compare results with those obtained in ERÎ² 1 and ERÎ± coexpressing models. Equally and perhaps more important is to determine the relevance of the biomarkers of ERÎ² 1 functionality, either unique gene signatures and/or individual genes, in breast cancer in vivo. Furthermore, when established as relevant, correlative studies of these biomarkers of ERÎ² 1 functionality with ERÎ² 1 expression in large (well powered statistically) well-annotated breast cancer cohorts with long clinical follow-up using standard protocols and cut points should be undertaken, perhaps using a international collaborative network approach.
Summary and Conclusions
Although ERÎ± remains today the primary target for endocrine therapies in breast cancer and seems to be the most critical in terms of development of the normal mammary gland, the widespread expression of ERÎ²-like proteins in both normal and neoplastic mammary tissues suggest that ERÎ² has a role in the breast. Little progress has been made in definitively elucidating this role. The presence of two ERs and their variant isoforms presents obvious challenges but also opportunities to tease out complexities in terms of understanding the estrogen signaling pathway in both normal and neoplastic breast tissues. The availability of more accurate tools, such as specific antibodies and the identification of downstream markers of functionality, will be significant in advancing knowledge in this field as well as determining relevance in human breast cancer in vivo.
The recognition of two distinct ERÎ²-expressing types of breast tumors in vivo and the possibility of differential function has already raised expectations that targeting ERÎ² in some cases may offer new treatment options for groups of breast cancer patients where previously only aggressive chemotherapies were available. If nothing else, this supports the continued efforts to understand the nature and function of ERÎ² in breast cancer, but it also suggests that ER status may need to be redefined to include an assessment of ERÎ² isoforms in addition to ERÎ±.
Acknowledgments ”¨This work was supported by the Canadian Institutes of Health Research (CIHR), the CancerCare Manitoba Foundation (CCMF), the Canadian Breast Cancer Foundation (CBCF), and the Canadian Breast Cancer Research Alliance (CBCRA).
Semin Reprod Med. 2012;30(1):5-13. © 2012 Thieme Medical Publishers
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