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The prognostic significance of ER-α 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-β in these lesions. Therefore, this study was performed to test the hypothesis that, in HUT lesions, the ratio of ER-α:ER-β 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-β1 and to ER-α. The data were compared with ER-β expression in all breast carcinomas that subsequently developed in the same patients as well as to ER-α expression in the corresponding tissues. In cases that progressed to carcinoma, the ratio of ER-α to ER-β 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-α negative and ER-β positive. Using both ER-β and ER-α 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-α and ER-β status of HUT lesions identified morphologically. The data support the hypothesis that high ER-α:ER-β levels characterize those cases within HUT likely to progress to breast cancer. The data also reveal that a reduced level of ER-β relative to ER-α is an accurate predictor of individual cases of HUT likely to progress to invasive breast carcinoma, thus supporting the concept that ER-α transcriptional activity is directly modulated by ER-β.