Expression of ER-{alpha}36, a novel variant of estrogen receptor {alpha}, and resistance to tamoxifen treatment in breast cancer.
PURPOSE Recently, a 36-kDa variant of estrogen receptor alpha (ER-alpha66), ER-alpha36, has been identified and cloned. ER-alpha36 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-alpha36 expression and tamoxifen resistance in patients with breast cancer. PATIENTS AND METHODS ER-alpha36 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-alpha36 was associated with poorer disease-free survival (DFS) and disease-specific survival (DSS) in patients with ER-alpha66-positive tumors who received tamoxifen treatment (chemotherapy plus tamoxifen or tamoxifen alone, n = 307). In contrast, ER-alpha36 was not associated with survival in patients with ER-alpha66-positive tumors who did not receive tamoxifen (chemotherapy alone, n = 129) and in patients with ER-alpha66-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-alpha36 was significantly associated with poorer DFS and DSS in 156 ER-alpha66-positive patients from this cohort, and ER-alpha36 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-alpha66-positive tumors that also express high levels of ER-alpha36 are less likely to benefit from tamoxifen treatment.
Shi
Liang
L
Breast Center, Beijing Cancer Hospital & Institute, Peking University School of Oncology, Beijing, 100036, PR China.
Dong
Bin
B
Li
Zhongwu
Z
Lu
Yunwei
Y
Ouyang
Tao
T
Li
Jinfeng
J
Wang
Tianfeng
T
Fan
Zhaoqing
Z
Fan
Tie
T
Lin
Benyao
B
Wang
Zhaoyi
Z
Xie
Yuntao
Y
D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D015331:Cohort Studies; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis / Q000517:prevention & control; D017698:Postmenopause / Q000378:metabolism; D013629:Tamoxifen / Q000627:therapeutic use* / Q000652:urine*
D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D013629:Tamoxifen