The cancer-testis gene, MEIOB, sensitizes triple-negative breast cancer to PARP1 inhibitors by inducing homologous recombination deficiency
| Autor: | Hongxia Wang, Jianshui Yang, Zhibin Hu, Yayun Gu, Cheng Wang, Wenwen Yuan, Yan Zhou, Na Qin, Xiaoan Liu, Hongbing Shen, Rongxuan Zhu, Yanhui Zhu, Hongxia Ma |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research Cell growth Poly ADP ribose polymerase Biology medicine.disease_cause medicine.disease In vitro 03 medical and health sciences 030104 developmental biology 0302 clinical medicine PARP1 Breast cancer Oncology 030220 oncology & carcinogenesis Cancer research medicine Carcinogenesis Gene Triple-negative breast cancer |
| Zdroj: | Cancer Biology and Medicine. 18:74-87 |
| ISSN: | 2095-3941 |
| DOI: | 10.20892/j.issn.2095-3941.2020.0071 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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