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

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