Estrogen receptor α and β profiling in human breast cancer

Balfe, Peter; McCann, Amanda; McGoldrick, Aloysius; McAllister, Katherine; Kennedy, M.; Dervan, P.; Kerin, Michael J.

doi:10.1016/j.ejso.2004.02.010

Cited by 31 publications

(19 citation statements)

References 24 publications

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“…Estrogen functions through binding to ER-a, one of the most important known prognostic markers for breast cancer [25,26]. A considerable effort has been made to study polymorphisms of ER-a, which may be a major regulator of ER-a expression.…”

Section: Discussionmentioning

confidence: 99%

Association of genetic polymorphisms of ER-α and the estradiol-synthesizing enzyme genes CYP17 and CYP19 with breast cancer risk in Chinese women

Zhang

Qian

et al. 2008

Breast Cancer Res Treat

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Estrogen plays a role in breast cancer development, and genetic polymorphisms in estrogen receptor gene ER-alpha and genes regulating estrogen biosynthesis and metabolisms are associated with the risk of breast cancer in women in western countries. Therefore, we hypothesized that SNPs in ER-alpha and other estrogen-metabolizing genes contribute to breast cancer risk in Chinese women. In this study, we genotyped polymorphisms in the regulatory regions of ER-alpha (rs3798577) and other two estrogen-metabolizing enzyme genes CYP17 (rs743572) and CYP19 (rs10046) among 300 breast cancer cases and 390 controls in a Chinese population. Crude and adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression analyses to estimate breast cancer risk associated with these polymorphisms. We found that the T allele frequency of ER-alpha was significantly higher in cases (59.8%) than controls (54.5%) (P = 0.047), but no significant difference was found in the genotype distribution. However, postmenopausal breast cancer risk was associated with the CYP17 TC genotype (aOR = 1.77, 95% CI = 1.11-2.83) compared with the TT genotype. The CYP19 variant TC + TT genotypes were associated with both overall cancer risk (TT + TC vs. TT aOR = 1.73, 95% CI = 1.13-2.65) and premenopausal cancer risk (TT + TC vs. TT aOR = 1.78, 95% CI = 1.03-3.09), particularly for ER +/PR + tumors. Furthermore, there were joint effects between CYP19 T and ER-alpha T variant genotypes (aOR = 1.67, 95% CI = 1.03-2.69 for CYP19 TC + TT vs. CC among ER-alpha T variant carriers) and between CYP19 T and CYP17 C variant genotypes (aOR = 1.77, 95% CI = 1.11-2.83 for CYP19 TC + TT vs. CC among CYP17 variant C carriers). This study provides evidence that polymorphisms CYP17 rs743572, CYP19 rs10046 and ER-alpha rs3798577 are associated with breast cancer risk among Chinese women.

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Section: Discussionmentioning

confidence: 99%

Association of genetic polymorphisms of ER-α and the estradiol-synthesizing enzyme genes CYP17 and CYP19 with breast cancer risk in Chinese women

Zhang

Qian

et al. 2008

Breast Cancer Res Treat

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“…The region of the mRNA targeted by primers may also influence which variants are detected. Several investigators have reported that ERβ mRNA levels often do not correlate with ERβ protein in breast tumor tissues [80][81][82][83][84], and confusion with ERβ status in tumors may result from this method. If fact, in one report only 54% of ERβ mRNA-positive tumors correlated with ERβ protein levels [84].…”

Section: Coexpression Of Erβ With Erα and Other Potential Markers In mentioning

confidence: 99%

“…Several investigators have reported that ERβ mRNA levels often do not correlate with ERβ protein in breast tumor tissues [80][81][82][83][84], and confusion with ERβ status in tumors may result from this method. If fact, in one report only 54% of ERβ mRNA-positive tumors correlated with ERβ protein levels [84]. Another method to measure functional ER protein, by ligand-binding assay with dextran-coated charcoal, seems to correlate well with ERα, but not necessarily with ERβ in tumors expressing only one ER subtype based on IHC [81].…”

Section: Coexpression Of Erβ With Erα and Other Potential Markers In mentioning

confidence: 99%

“…In contrast, ERβ mRNA levels are either unchanged or increased in ERα− tumors from African American women (n=6) [118]. However, these are small studies and the results need to be confirmed with additional patients and IHC, particularly as ERβ protein does not correlate with mRNA in several studies [80][81][82][83][84]. If apparent mRNA trends are verified at the protein level, it would suggest that ER+ tumors in different ethnic groups could have different clinical phenotypes and responses to endocrine therapy.…”

Section: Clinical Correlations Between Erβ Expression and Patient Popmentioning

confidence: 99%

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ERβ in breast cancer—Onlooker, passive player, or active protector?

2008

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The role of estrogen exposure in breast cancer risk is well-documented, and both estrogen synthesis and actions through the estrogen receptor (ER) have been targeted by therapies to control hormonedependent breast cancer. The discovery of a second ER form and its therapeutic implications sparked great interest. Both the original ERα and the more recently identified ERβ subtypes bind and respond similarly to many physiological and pharmacological ligands. However, differences in phytoestrogen binding have been noted, and subtype-specific ligands have been developed. Cell-based assays show that ERβ and its variants are generally less active on gene transcription than ERα, and may influence ERα activity; however, both gene-and cell-specific responses occur, and nongenomic activities are less well explored. Specific ligands, and methods to disrupt or eliminate receptor subtype expression in animal and cell models, demonstrate that the ERs have both overlapping and distinct biological functions. Overall, in cell-based studies, ERα appears to play a predominant role in cell proliferation, and ERβ is suggested to be antiproliferative.The potential for distinct populations of breast tumors to be identified based on ER subtype expression, and to exhibit distinct clinical behaviors, is of greatest interest. Several studies suggest that the majority of ER-positive tumors contain both subtypes, but that some tumors contain only ERβ and may have distinct clinical behaviors and responses. Expression of ERβ together with ERα favors positive responses to endocrine therapy in most studies, and additional studies to determine if the addition of ERβ to ERα as a tumor marker is of clinical benefit are warranted. In contrast, the positive association between ERβ and HER2 expression in high-grade ERα-negative breast cancer does not favor positive responses to endocrine therapy. Expression of ERβ in specific clinical subpopulations, and the potential for therapies targeting ERβ specifically, is discussed.

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“…Both receptors exert opposite effects in the activator protein 1 (AP-1) signaling pathway. ER-a activates transcription while ER-b inhibits it (Balfe et al 2004). Two ER-b cohorts exist; one is coexpressed with ER-a, and the other is not.…”

Section: In Vitro Studiesmentioning

confidence: 99%

Tocotrienols and breast cancer: the evidence to date

et al. 2011

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Breast cancer is the second most frequent cancer affecting women worldwide after lung cancer. The toxicity factor associated with synthetic drugs has turned the attention toward natural compounds as the primary focus of interest as anticancer agents. Vitamin E derivatives consisting of the well-established tocopherols and their analogs namely tocotrienols have been extensively studied due to their remarkable biological properties. While tocopherols have failed to offer protection, tocotrienols, in particular, a-, d-, and c-tocotrienols alone and in combination have demonstrated anticancer properties. The discovery of the antiangiogenic, antiproliferative, and apoptotic effects of tocotrienols, as well as their role as an inducer of immunological functions, not only reveals a new horizon as a potent antitumor agent but also reinforces the notion that tocotrienols are indeed more than antioxidants. On the basis of a transcriptomic platform, we have recently demonstrated a novel mechanism for tocotrienol activity that involves estrogen receptor (ER) signaling. In silico simulations and in vitro binding analyses indicate a high affinity of specific forms of tocotrienols for ERb, but not for ERa. Moreover, we have demonstrated that specific tocotrienols increase ERb translocation into the nucleus which, in turn, activates the expression of estrogenresponsive genes (MIC-1, EGR-1 and Cathepsin D) in breast cancer cells only expressing ERb cells (MDA-MB-231) and in cells expressing both ER isoforms (MCF-7). The binding of specific tocotrienol forms to ERb is associated with the alteration of cell morphology, caspase-3 activation, DNA fragmentation, and apoptosis. Furthermore, a recently concluded clinical trial seems to suggest that tocotrienols in combination with tamoxifen may have the potential to extend breast cancer-specific survival.

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Estrogen receptor α and β profiling in human breast cancer

Cited by 31 publications

References 24 publications

Association of genetic polymorphisms of ER-α and the estradiol-synthesizing enzyme genes CYP17 and CYP19 with breast cancer risk in Chinese women

Association of genetic polymorphisms of ER-α and the estradiol-synthesizing enzyme genes CYP17 and CYP19 with breast cancer risk in Chinese women

ERβ in breast cancer—Onlooker, passive player, or active protector?

Tocotrienols and breast cancer: the evidence to date

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