Originally published as JCO Early Release 10.1200/JCO.2008.17.2254 on June 1 2009

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Expression of ER-36, a Novel Variant of Estrogen Receptor , and Resistance to Tamoxifen Treatment in Breast Cancer

From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Breast Center, and Department of Pathology, Beijing Cancer Hospital and Institute, Peking University School of Oncology, Beijing, China; and Departments of Surgery and Pathology, Creighton University Medical School, Omaha, NE.

Corresponding author: Yuntao Xie, MD, PhD, Breast Center, Beijing Cancer Hospital & Institute, Peking University School of Oncology, Beijing, 100036, P.R. China, e-mail: zlxyt2{at}bjmu.edu.cn.

Purpose Recently, a 36-kDa variant of estrogen receptor (ER-66), ER-36, has been identified and cloned. ER-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-36 expression and tamoxifen resistance in patients with breast cancer.

Patients and Methods ER-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-36 was associated with poorer disease-free survival (DFS) and disease-specific survival (DSS) in patients with ER-66–positive tumors who received tamoxifen treatment (chemotherapy plus tamoxifen or tamoxifen alone, n = 307). In contrast, ER-36 was not associated with survival in patients with ER-66–positive tumors who did not receive tamoxifen (chemotherapy alone, n = 129) and in patients with ER-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-36 was significantly associated with poorer DFS and DSS in 156 ER-66–positive patients from this cohort, and ER-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-66–positive tumors that also express high levels of ER-36 are less likely to benefit from tamoxifen treatment.

Supported by the Program for New Century Excellent Talents in University (Grant No. 985-2-067-113 to Dr. Yuntao Xie) and a grant from the National Natural Science Foundation of China (Grant No. 30672419). This study was also supported by National Institutes of Health Grant No. DK070016 (Z.Y.W.), the Susan G. Komen Breast Cancer Foundation Grant No. BCTR81906 (Z.Y.W.), and the Nebraska Tobacco Settlement Biomedical Research Program Award (Grant No. LB-595; Z.Y.W.).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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