title: MiR-4653-3p and its target gene FRS2 are prognostic biomarkers for hormone receptor positive breast cancer patients receiving tamoxifen as adjuvant endocrine therapy.
abstract: 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.
authors.affiliation: Laboratory 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.
authors.forename: XiaoRong
authors.initials: X
authors.lastname: Zhong
authors.affiliation: Laboratory 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.
authors.forename: GuiQin
authors.initials: G
authors.lastname: Xie
authors.affiliation: Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, P. R. China.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Laboratory 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.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Laboratory 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.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Laboratory 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.
authors.forename: YanPing
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, P. R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu 610041, P. R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, P. R. China.|Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu 610041, P. R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Bu
authors.affiliation: Department of Epidemiology and Bio-Statistics, West China School of Public Health, Sichuan University, Chengdu 610041, P. R. China.
authors.forename: JiaYuan
authors.initials: J
authors.lastname: Li
authors.affiliation: Laboratory 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.|Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, P. R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
mesh_terms: D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D002681:China; D015331:Cohort Studies; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D015398:Signal Transduction; D013629:Tamoxifen / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; C106534:FRS2 protein, human; D008565:Membrane Proteins; D035683:MicroRNAs; D013629:Tamoxifen
keywords: FRS2; breast cancer; miR-4653-3p; prognostic biomarker; tamoxifen resistant