Low Levels of Estrogen Receptor β Protein Predict Resistance to Tamoxifen Therapy in Breast Cancer

Purpose: Breast cancer is a hormone-dependent cancer, and the presence of estrogen receptor α (ER-α) in tumors is used clinically to predict the likelihood of response to hormonal therapies. The clinical value of the second recently identified ER isoform, called ER-β, is less clear, and there is currently conflicting data concerning its potential role as a prognostic or predictive factor. Experimental Design: To assess whether ER-β expression is associated with clinical outcome, protein levels were measured by immunoblot analysis of a retrospective bank of tumor cell lysates from 305 axillary node-positive patients. A total of 119 received no adjuvant therapy, and 186 were treated with tamoxifen only. The median follow-up time was 65 months. Univariate and multivariate Cox regression modeling was done to assess the prognostic and predictive significance of ER-β expression. Results: Expression of ER-β protein did not correlate significantly with any other clinical variables, including ER and progesterone levels (as measured ligand binding assay), tumor size, age, or axillary nodal status. In the untreated population, those patients whose tumors who expressed both receptor isoforms exhibited the most favorable outcome as compared with those patients who had lost ER-α expression. However, there was no association between ER-β levels alone and either disease-free or overall survival in the untreated patient population. In contrast, in both univariate and multivariate analyses, high levels of ER-β predicted an improved disease-free and overall survival in patients treated with adjuvant tamoxifen therapy. Conclusions: These findings provide evidence that ER-β may be an independent predictor of response to tamoxifen in breast cancer. Furthermore, these results suggest that ER-β may influence tumor progression in ways different from those mediated by the ER-α isoform.