Expression of Estrogen Receptor (ER) βcx Protein in ERα-positive Breast Cancer Specific Correlation with Progesterone Receptor

Estrogen receptor (ER) βcx, a splice variant of ERβ, is a dominant repressor of ERα function. In this study we investigated the possibility that because the progesterone receptor ( PR ) gene is a downstream target of activated ERα, in ERα-positive breast cancers, expression of ERβcx would result in repression of PR. In ERα-positive MCF-7 cells, stable transfection of an ERβcx expression vector resulted in reduced expression of PR without affecting ERα expression. In breast cancers, immunohistochemical evaluation of ERα-positive foci for the expression of PR and ERβcx revealed a significant correlation between a PR-negative phenotype and the presence of ERβcx within the foci. However, when entire lesions were evaluated by Allred scoring in 115 ERα-positive breast cancer specimens, the presence of two distinct groups of patients could be discerned. One group expressed ERβcx and had very reduced levels of PR expression, as expected. The second group showed both ERβcx and high levels of PR. To evaluate the role of ERβcx in sensitivity to tamoxifen, 18 core needle biopsies, obtained before preoperative treatment with tamoxifen, were investigated. The results show that expression of ERβcx in primary lesions correlated with a poor response to tamoxifen, especially in cancers with a low PR expression in Allred score. This is the first evidence that evaluation of ERβcx along with PR may contribute to a better characterization of ERα-positive breast cancers.