2. Academic Validation
  3. DAXX, as a Tumor Suppressor, Impacts DNA Damage Repair and Sensitizes BRCA-Proficient TNBC Cells to PARP Inhibitors

DAXX, as a Tumor Suppressor, Impacts DNA Damage Repair and Sensitizes BRCA-Proficient TNBC Cells to PARP Inhibitors

  • Neoplasia. 2019 Jun;21(6):533-544. doi: 10.1016/j.neo.2019.04.001.
Yaqin Shi 1,  Juan Jin 2,  Xin Wang 3,  Wenfei Ji 4,  Xiaoxiang Guan 5
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China. Electronic address: shiyaqinand@126.com.
  • 2 Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China. Electronic address: medjinjuan@126.com.
  • 3 Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China. Electronic address: lotus_wx@126.com.
  • 4 Department of Medical Oncology, Jinling Hospital, Nanjing Medical University, Nanjing 210002, China. Electronic address: jiwenfei1117@gmail.com.
  • 5 Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China; Department of Medical Oncology, Jinling Hospital, Nanjing Medical University, Nanjing 210002, China; Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China. Electronic address: xguan@nju.edu.cn.
PMID: 31029033 DOI: 10.1016/j.neo.2019.04.001
Abstract

Treatment options are limited for patients with triple negative breast Cancer (TNBC). Understanding genes that participate in Cancer progression and DNA damage response (DDR) may improve therapeutic strategies for TNBC. DAXX, a death domain-associated protein, has been reported to be critically involved in Cancer progression and drug sensitivity in multiple Cancer types. However, its role in breast Cancer, especially for TNBC, remains unclear. Here, we demonstrated a tumor suppressor function of DAXX in TNBC proliferation, colony formation, and migration. In Mouse Xenograft Models, DAXX remarkably inhibited tumorigenicity of TNBC cells. Mechanistically, DAXX could directly bind to the promoter region of RAD51 and impede DNA damage repair, which impacted the protection mechanism of tumor cells that much depended on remaining DDR pathways for cell growth. Furthermore, DAXX-mediated inefficient DNA damage repair could sensitize BRCA-proficient TNBC cells to PARP inhibitors. Additionally, we identified that dual RAD51 and PARP inhibition with RI-1 and ABT888 significantly reduced TNBC growth both in vitro and in vivo, which provided the first evidence of combining RAD51 and PARP inhibition in BRCA-proficient TNBC. In conclusion, our data support DAXX as a modulator of DNA damage repair and suppressor of TNBC progression to sensitize tumors to the PARP Inhibitor by repressing RAD51 functions. These provide an effective strategy for a better application of PARP inhibition in the treatment of TNBC.

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