Expression of estrogen receptor (ER) βcx protein in ERα-positive breast cancer : Specific correlation with progesterone receptor

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