Association of ERβ2/ERβcx with outcome of adjuvant endocrine treatment for primary breast cancer-a retrospective study

Clatterbridge Cancer Research Trust, J.K. Douglas Laboratories, Clatterbridge Hospital, Bebington, Wirral, Merseyside, UK.
BMC Cancer (Impact Factor: 3.36). 02/2007; 7(1):131. DOI: 10.1186/1471-2407-7-131
Source: PubMed


Oestrogen receptor beta (ERbeta) modulates ERalpha activity; wild type ERbeta (ERbeta1) and its splice variants may therefore impact on hormone responsiveness of breast cancer. ERbeta2/ERbetacx acts as a dominant negative inhibitor of ERalpha and expression of ERbeta2 mRNA has been proposed as a candidate marker for outcome in primary breast cancer following adjuvant endocrine therapy. We therefore now assess ERbeta2 protein by immunostaining and mRNA by quantitative RT-PCR in relation to treatment outcome.
ERbeta2-specific immunostaining was quantified in 141 primary breast cancer cases receiving adjuvant endocrine therapy, but no neoadjuvant therapy or adjuvant chemotherapy. The expression of mRNA for ERbeta2/ERbetacx was measured in 100 cases by quantitative RT-PCR. Statistical analysis of breast cancer relapse and breast cancer survival was performed using Kaplan Meier log-rank tests and Cox's univariate and multivariate survival analysis.
High ERbeta2 immunostaining (Allred score >5) and high ERbeta2 mRNA levels were independently associated with significantly better outcome across the whole cohort, including both ERalpha positive and negative cases (Log-Rank P < 0.05). However, only ERbeta2 mRNA levels were significantly associated with better outcome in the ERalpha + subgroup (Log-Rank P = 0.01) and this was independent of grade, size, nodal status and progesterone receptor status (Cox hazard ratio 0.31 P = 0.02 for relapse; 0.17 P = 0.01 for survival). High ERbeta2 mRNA was also associated with better outcome in node negative cases (Log Rank P < 0.001).ERbeta2 protein levels were greater in ERalpha positive cases (T-test P = 0.00001), possibly explaining the association with better outcome. Levels of ERbeta2 protein did not correlate ERbeta2 mRNA levels, but 34% of cases had both high mRNA and protein and had a significantly better outcome (Log-Rank relapse P < 0.005).
High ERbeta2 protein levels were associated with ERalpha expression. Although most cases with high ERbeta2 mRNA had strong ERbeta2 immunostaining, mRNA levels but not protein levels were independently predictive of outcome in tamoxifen-treated ERalpha + tumours. Post-transcriptional control needs to be considered when assessing the biological or clinical importance of ERbeta proteins.

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    • "All these strongly suggest that TT genotype of rs1271572 is a functionally important SNP in breast cancer. Our finding that ERβ is related to a favorable outcome is consistent with previous report by of Vinayagam et al. [27]. "
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    ABSTRACT: Background To characterize single nucleotide polymorphisms (SNPs) within the promoter region of the estrogen receptor beta (ERβ) gene and to analyze the association of ERβ SNPs with susceptibility to breast cancer. Genotype frequencies of five SNPs (rs3020449, rs3020450, rs2987983, rs1271572 and rs1887994) in the promoter region of the ERβ gene in 873 women with breast cancer, 645 women with fibroadenoma and 700 healthy women were determined using an allele-specific tetra-primer polymerase chain reaction (PCR). Kaplan-Meier survival analysis was performed to evaluate the association of selected rs1271572 with prognosis in breast cancer. Electrophoretic mobility-shift assays were conducted to explore the binding of SNP rs1271572 containing probes to transcriptional factor Ying Yang 1 (YY1). Results Women with the homozygous TT genotype of rs1271572 had a significantly higher risk in developing breast cancer. Breast cancer patients with the TT genotype of rs1271572 had lower five-year survival rates than those with other genotypes and were more likely to suffer brain metastases. The rs1271572 G→T SNP abrogated YY1 binding and reduced the transcription activity of the promoter 0 N in the ERβ gene in vitro. Conclusions TT genotype of rs1271572 is associated with increased risk for breast cancer in Chinese women and is associated with unfavored prognosis in Chinese breast cancer patients. TT genotype of rs1271572 inhibited expression of ERβ gene by down regulating transcriptional activity of the promoter 0 N in the ERβ gene. Our data revealed that the TT genotype of rs1271572 resulted in loss of the YY1 binding site and reduced the transcription activity of the promoter 0 N in the ERβ gene.
    Journal of Biomedical Science 05/2013; 20(1):32. DOI:10.1186/1423-0127-20-32 · 2.76 Impact Factor
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    • "Five did not find a correlation of ERb2 with any clinical outcome or survival [12] [14] [56] [60] [63]. Two investigations showed ERb2 as a poor prognosticator [58] [64], whereas two others found ERb2 associated with better outcomes [59] [61]. In one study, which also analyzed expression of progesterone receptor (PR), the presence of PR was found to associate with responsiveness to tamoxifen irrespective of ERb2 level [65], but in a subset of PR-negative samples, ERb2 expression was a predictor of resistance to tamoxifen [65]. "
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    ABSTRACT: Estrogen receptor (ER) β was discovered over a decade ago. The design of most studies on this receptor was based on knowledge of its predecessor, ERα. Although breast cancer (BCa) has been a main focus of ERβ research, its precise roles in breast carcinogenesis remain elusive. Data from in vitro models have not always matched those from observational or clinical studies. Several inherent factors may contribute to these discrepancies: (a) several ERβ spliced variants are expressed at the protein level, and isoform-specific antibodies are unavailable for some variants; (b) post-translational modifications of the receptor regulate receptor functions; (c) the role of the receptor differs significantly depending on the type of ligands, cis-elements, and co-regulators that interact with the receptor; and (d) the diversity of distribution of the receptor among intracellular organelles of BCa cells. This review addresses the gaps in knowledge in ERβ research as it pertains to BCa regarding the following questions: (1) is ERβ a tumor suppressor in BCa?; (2) do ERβ isoforms play differential roles in breast carcinogenesis?; (3) do nuclear signaling and extranuclear ERβ signaling differ in BCa?; (4) what are the consequences of post-translational modifications of ERβ in BCa?; (5) how do co-regulators and interacting proteins increase functional diversity of ERβ?; and (6) how do the types of ligand and regulatory cis-elements affect the action of ERβ in BCa?. Insights gained from these key questions in ERβ research should help in prevention, diagnosis/prognosis, and treatment of BCa.
    Steroids 03/2012; 77(7):727-37. DOI:10.1016/j.steroids.2012.03.008 · 2.64 Impact Factor
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    • "However , in contrast to these studies, various other studies including the present one have measured ERb expression levels on the mRNA and not on the protein level and have reported significant correlations of ERb2 mRNA expression levels with clinical outcome [12] [49] [50]. Moreover, in studies in which ERb was determined by IHC and RT-PCR [22] [33] [51] ERb2 mRNA has also been shown to be a predictor of good clinical outcome. The lack of correlations of ERb mRNA with protein levels may be at least in part due to the use of different measuring strategies with proteins being usually determined by IHC and mRNA from tissue extracts by RT-PCR. "
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    ABSTRACT: In breast cancer, little is known about the consequences of co-expression of ERα with the second estrogen receptor, ERβ, and its isoforms in light of their joint prognostic value. Previously reported correlations have been based mostly on independent ERα and ERβ expression levels in breast tumors. To address whether the expression ratio of ERα and ERβ and its isoforms may be a more important parameter than their absolute levels, we analyzed relative mRNA expression ratios of ERβ1 to ERβ2 and ERα in 74 clinical samples of invasive breast cancer including 39 early-onset and 35 late-onset breast cancers. Expression levels were correlated with clinical and histopathological parameters and disease-free interval. A specific correlation of ERβ1 expression levels with tumor size was detected in early-onset breast cancer patients and of ERβ2 levels with tumor size in late-onset patients. Expression of both ERβ isoforms inversely correlated with expression of the two estrogen regulated genes, progesterone receptor and pS2 in both groups. Higher levels of ERβ2 than ERβ1 isoform were associated with a better outcome in late-onset patients. Our results suggest that different isoforms of ERβ may be involved in suppression of tumor growth in young and elder patients and may have different prognostic values.
    Cancer letters 02/2012; 321(1):73-9. DOI:10.1016/j.canlet.2012.02.022 · 5.62 Impact Factor
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