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

• 作者: Yayun Gu Cheng Wang Rongxuan Zhu Jianshui Yang Wenwen Yuan Yanhui Zhu Yan Zhou Na Qin Hongbing Shen Hongxia Ma Hongxia Wang Xiaoan Liu Zhibin Hu
• 来源期刊: 癌症生物学与医学（英文版）
• 年，卷（期）: 2021,（1）
• 所属期刊栏目: ORIGINAL ARTICLE
• 页码范围: 74-87
• 页数: 14页
• 语种: 英文
• DOI: 10.20892/j.issn.2095-3941.2020.0071

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 polyADP-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.