MiR-4653-3p and its target gene FRS2 are prognostic biomarkers for hormone receptor positive breast cancer patients receiving tamoxifen as adjuvant endocrine therapy
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XiaoRong Zhong1,*, GuiQin Xie1,*, Zhang Zhang2,*, Zhu Wang1, Yu Wang1, YanPing Wang1, Yan Qiu2, Li Li3, Hong Bu2,3, JiaYuan Li4, Hong Zheng1,5
1Laboratory of Molecular Diagnosis of Cancer, State Key Laboratory of Biotherapy, National Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, P. R. China
2Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, P. R. China
3Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu 610041, P. R. China
4Department of Epidemiology and Bio-Statistics, West China School of Public Health, Sichuan University, Chengdu 610041, P. R. China
5Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, P. R. China
*These authors contributed equally to this work
Hong Zheng, email: [email protected]
Keywords: miR-4653-3p, FRS2, breast cancer, tamoxifen resistant, prognostic biomarker
Received: December 08, 2015 Accepted: August 08, 2016 Published: August 13, 2016
Long-term tamoxifen treatment significantly improves the survival of hormone receptor-positive (HR+) breast cancer (BC) patients. However, tamoxifen resistance remains a challenge. We aimed to identify prognostic biomarkers for tamoxifen resistance and reveal the underlying mechanism. From March 2001 to September 2013, 400 HR+ BC women (stage I~III) were treated with adjuvant tamoxifen for 5 years or until relapse in West China Hospital. We included a discovery set of 6 patients who were refractory to tamoxifen, and a validation cohort of 88 patients including 35 cases with relapse. In the discovery set, microRNA microarray showed that miR-4653-3p decreased in recurrent/metastatic lesions compared to the matched primary lesions. In the validation cohort, real-time RT-PCR demonstrated that, following tamoxifen treatment, miR-4653-3p overexpression in the primary tumors decreased the risk of relapse (adjusted hazard ratio [HR] = 0.17, 95% confidence interval [CI] = 0.05~0.57, P = 0.004). Conversely, high expression of FRS2, the key adaptor protein required by FGFR signaling, predicted poor disease-free survival (DFS) (adjusted HR = 2.70, 95% CI = 1.11~6.56, P = 0.03). MiR-4653-3p down regulated FRS2 by binding to its 3’ untranslated region. Either overexpressing miR-4653-3p or attenuating FRS2 expression could restore TAM sensitivity in two tamoxifen-resistant BC cell lines. In conclusion, high miR-4653-3p level was the potential predictor for favorable DFS, while FRS2 overexpression was potential high-risk factor for relapse in HR+ BC patients receiving TAM adjuvant therapy. FGFR/FRS2 signaling might be a promising target for reversing tamoxifen resistance.
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