Expression of ER-a36, a novel variant of estrogen receptor a, and resistance to tamoxifen treatment in breast cancer.

Abstract

#3037 Background: Recently, a 36 kDa variant of estrogen receptor a (ER-a66), ER-a36, has been identified and cloned. ER-a36 predominantly localizes on the plasma membrane and in the cytoplasm and mediates a membrane-initiated “nongenomic” signaling pathway. In this study, we investigated the association between ER-a36 expression and tamoxifen resistance in breast cancer patients.
 Methods: ER-a36 protein expression in tumors from 710 breast cancer patients with a median follow-up of 7.9 years was assessed using immunohistochemistry (IHC) assay. Survival curves were compared using the log-rank test and multivariate analysis was performed using Cox model. All statistical tests were two-sided.
 Results: Among the patients with ER-a66 positive tumors who received tamoxifen treatment (n=307), overexpression of ER-a36 was associated with poorer disease-free survival (DFS) and disease-specific survival (DSS) and remained as an unfavorable independent factor of survival in multivariate analyses (DFS: HR=2.27; 95% CI= 1.40 to 3.68; P=. 001; DSS: HR=2.42; 95% CI= 1.37 to 4.28; P= .002). In contrast, among patients with ER-a66 positive tumors who did not receive tamoxifen (n=129), ER-a36 expression was not associated with survival, indicating a correlation between ER-a36 expression and tamoxifen resistance. Furthermore, ER-a36 expression was not associated with survival in ER-a66 negative tumors whether the patients received tamoxifen (n=73) or not (n=149). Our in vitro experiments with MCF7/ER36 cells also confirmed that high ER-a36 expression resulted in tamoxifen resistance.
 Conclusions: Patients with ER-a66 positive tumors that also express high levels of ER-a36 are less likely to benefit from tamoxifen treatment. ER-a36 is an important predictive marker for tamoxifen therapy in ER-a66 positive breast cancer patients. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3037.

Induction of estrogen receptor α-36 expression by bone morphogenetic protein 2 in breast cancer cell lines

“…Recent studies have indicated that the efficacy of endocrine therapy cannot be simply explained by the expression levels of ERα, but may be determined by the expression profiles of both ERα and ERβ, as well as their various splice variants (14,21,24,25). Furthermore, to understand the meaning of the demonstrated change in ERα-36 expression induced by BMP2 in breast cancer cells, additional research should be carried out to determine whether the ERα-36 reported in the present study is the same as that reported by Wang et al (21).…”

Daidzein–Estrogen Interaction in the Rat Uterus and Its Effect on Human Breast Cancer Cell Growth

“…For instance, subtle differences in ER conformations caused by (1) interaction with different ligands interacting with different co-activators or co-repressors within the cell; 50 (2) the existence of spliced receptor variants such as ER36 51,52 or ER46; 53 (3) recruitment of co-regulators by the orphan nuclear ERRa in a ligand-independent manner, 54-56 thus decreasing their availability for interaction with remaining ERs in some cell types but not others; (4) presence of different molecular chaperones such as FKBP51, FKBP52, and Cyp40, which may be incorporated in the inactivated ER complexes from the different cell types; 57,58 or simply, (5) that some of the responses are not ER-mediated responses. In the case of differences between human breast cancer cell lines MCF-7 and MDA-MB-231, differences had been explained by the role of the ERa46 isoform in cellular proliferation.…”

Endocrine Resistance and Epithelial Mesenchymal Transition in Breast Cancer

“…The presence of ER variants was also hypothesized to have a role in endocrine resistance. A reduced response to endocrine therapy has been associated with the presence of a new truncated variant of ER, ER36, in addition to the full-length receptor (Shi et al, 2009). …”