Expression of ER-α36, a Novel Variant of Estrogen Receptor α, and Resistance to Tamoxifen Treatment in Breast Cancer

Purpose Recently, a 36-kDa variant of estrogen receptor alpha (ER-alpha 66), ER-alpha 36, has been identified and cloned. ER-alpha 36 predominantly localizes on the plasma membrane and in the cytoplasm and mediates a membrane-initiated "nongenomic" signaling pathway. Here, we investigate the association between ER-alpha 36 expression and tamoxifen resistance in patients with breast cancer. Patients and Methods ER-alpha 36 protein expression in tumors from 896 women (two independent cohorts, 1 and 2) with operable primary breast cancer was assessed using an immunohistochemistry assay. Results In the first cohort of 710 consecutive patients, overexpression of ER-alpha 36 was associated with poorer disease-free survival (DFS) and disease-specific survival (DSS) in patients with ER-alpha 66 positive tumors who received tamoxifen treatment (chemotherapy plus tamoxifen or tamoxifen alone, n = 307). In contrast, ER-alpha 36 was not associated with survival in patients with ER-alpha 66 positive tumors who did not receive tamoxifen (chemotherapy alone, n = 129) and in patients with ER-alpha 66-negative tumors whether they received tamoxifen (n = 73) or not (n = 149). In the second cohort of 186 patients who only received tamoxifen as adjuvant therapy, overexpression of ER-alpha 36 was significantly associated with poorer DFS and DSS in 156 ER-alpha 66-positive patients from this cohort, and ER-alpha 36 remained an independent unfavorable factor for both DFS and DSS in these 156 patients by a multivariate analysis (DFS: hazard ratio [HR] = 5.47; 95% CI, 1.81 to 16.51; P = .003; DSS: HR = 13.97; 95% CI, 1.58 to 123.53; P = .018). Conclusion Women with ER-alpha 66-positive tumors that also express high levels of ER-alpha 36 are less likely to benefit from tamoxifen treatment.