Prognostic significance of estrogen receptor Beta in epithelial hyperplasia of usual type with known outcome.

The prognostic significance of ER-alpha expression in benign proliferative breast disease has been confirmed in epithelial hyperplasia of usual type (HUT). However, little is known about the role of ER-beta in these lesions. Therefore, this study was performed to test the hypothesis that, in HUT lesions, the ratio of ER-alpha:ER-beta is an accurate determinant of breast cancer risk and of predicting subsequent progression to invasive breast cancer. This case-control study analyzed a cohort of benign proliferative breast lesions and foci of ductal HUT in 117 patients with long follow-up (20 years). These foci were analyzed by morphometric image analysis together with immunohistochemistry using monoclonal antibodies to ER-beta1 and to ER-alpha. The data were compared with ER-beta expression in all breast carcinomas that subsequently developed in the same patients as well as to ER-alpha expression in the corresponding tissues. In cases that progressed to carcinoma, the ratio of ER-alpha to ER-beta in HUT was significantly higher (P < 0.001) than in those that did not progress. None of the HUT foci from patients who progressed to breast cancer were simultaneously ER-alpha negative and ER-beta positive. Using both ER-beta and ER-alpha in a logistic model demonstrated a 75% correct classification rate for the cohort studied. These findings confirm the diagnostic and prognostic value of defining the ER-alpha and ER-beta status of HUT lesions identified morphologically. The data support the hypothesis that high ER-alpha:ER-beta levels characterize those cases within HUT likely to progress to breast cancer. The data also reveal that a reduced level of ER-beta relative to ER-alpha is an accurate predictor of individual cases of HUT likely to progress to invasive breast carcinoma, thus supporting the concept that ER-alpha transcriptional activity is directly modulated by ER-beta.