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The cancer-testis gene,MEIOB,sensitizes triple-negative breast cancer to PARP1 inhibitors by inducing homologous recombination deficiency

查看全文 作　　者：Yayun [1,2]Gu;Cheng [1,2,3]Wang;Rongxuan [4]Zhu;Jianshui [1]Yang;Wenwen [1,2]Yuan;Yanhui [5]Zhu;Yan [1,2]Zhou;Na [1,2]Qin;Hongbing [1,2]Shen;Hongxia [1,2]Ma;Hongxia [4]Wang;Xiaoan [5]Liu;Zhibin [1,2]Hu 高影响力作者 机构地区：[1]State Key Laboratory of Reproductive Medicine,Center for Global Health,School of Public Health,Nanjing Medical University,Nanjing 211166,China;[2]Jiangsu Key Lab of Cancer Biomarkers,Prevention and Treatment,Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine,Nanjing Medical University,Nanjing 211116,China;[3]Department of Bioinformatics,School of Biomedical Engineering and Informatics,Nanjing Medical University,Nanjing 211166,China;[4]Department of Oncology,Shanghai General Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200080,China;[5]Department of Breast Surgery,The First Affiliated Hospital with Nanjing Medical University,Nanjing 210029,China高影响力机构 出　　处：《Cancer Biology & Medicine》索引2021年第18卷第1期,共14页高影响力期刊 基　　金：supported by the National Natural Science Foundation of China(Grant Nos.81902836 and 81572602);the China Postdoctoral Science Foundation(Grant Nos.2017M610339 and 2018M630584)。 摘　　要：Objective:The newly defined cancer-testis(CT)gene,MEIOB,was previously found to play key roles in DNA double-strand break(DSB)repair.In this study,we aimed to investigate the effects and mechanisms of MEIOB in the carcinogenesis of triple-negative breast cancers(TNBCs).Methods:The Cancer Genome Atlas database was used to quantify the expression of MEIOB.Cox regression analysis was used to evaluate the association between MEIOB expression and the prognosis of human TNBC.The effects of MEIOB on cell proliferation and migration in TNBCs were also assessed in vitro.Patient-derived xenograft(PDX)models were used to assess the sensitivity of breast cancers with active MEIOB to PARP1 inhibitors.Results:We confirmed MEIOB as a CT gene whose expression was restricted to the testes and breast tumors,especially TNBCs.Its activation was significantly associated with poor survival in breast cancer patients[overall,hazard ratio(HR)=1.90(1.16–2.06);TNBCs:HR=7.05(1.16–41.80)].In addition,we found that MEIOB was oncogenic and significantly promoted the proliferation of TNBC cells.Further analysis showed that MEIOB participated in DSB repair in TNBCs.However,in contrast to its function in meiosis,it mediated homologous recombination deficiency(HRD)through the activation of poly ADP-ribose polymerase(PARP)1 by interacting with YBX1.Furthermore,activated MEIOB was shown to confer sensitivity to PARP inhibitors,which was confirmed in PDX models.Conclusions:MEIOB played an oncogenic role in TNBC through its involvement in HRD.In addition,dysregulation of MEIOB sensitized TNBC cells to PARP inhibitors,so MEIOB may be a therapeutic target of PARP1 inhibitors in TNBC. 关 键 词：Cancer-testis gene MEIOB triple-negative breast cancer PARP1 inhibitor cell proliferation
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