RAD51AP1 deficiency reduces tumor growth by targeting stem cell self-renewal

Allison Elaine Bridges, Sabarish Ramachandran, Rajneesh Pathania, Utkarsh Parwal, Adrienne Lester, Pragya Rajpurohit, Daley S. Morera, Nikhil Patel, Nagendra Singh, Hasan Korkaya, Santhakumar Manicassamy, Puttur D. Prasad, Vinata B Lokeshwar, Balakrishna L Lokeshwar, Vadivel Ganapathy, Muthusamy Thangaraju

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

RAD51-associated protein 1 (RAD51AP1) plays an integral role in homologous recombination by activating RAD51 recombinase. Homologous recombination is essential for preserving genome integrity and RAD51AP1 is critical for D-loop formation, a key step in homologous recombination. Although RAD51AP1 is involved in maintaining genomic stability, recent studies have shown that RAD51AP1 expression is significantly upregulated in human cancers. However, the functional role of RAD51AP1 in tumor growth and the underlying molecular mechanism(s) by which RAD51AP1 regulates tumorigenesis have not been fully understood. Here, we use Rad51ap1-knockout mice in genetically engineered mouse models of breast cancer to unravel the role of RAD51AP1 in tumor growth and metastasis. RAD51AP1 gene transcript was increased in both luminal estrogen receptor-positive breast cancer and basal triple-negative breast cancer, which is associated with poor prognosis. Conversely, knockdown of RAD51AP1 (RADP51AP1 KD) in breast cancer cell lines reduced tumor growth. Rad51ap1-deficient mice were protected from oncogene-driven spontaneous mouse mammary tumor growth and associated lung metastasis. In vivo, limiting dilution studies provided evidence that Rad51ap1 plays a critical role in breast cancer stem cell (BCSC) self-renewal. RAD51AP1 KD improved chemotherapy and radiotherapy response by inhibiting BCSC self-renewal and associated pluripotency. Overall, our study provides genetic and biochemical evidences that RAD51AP1 is critical for tumor growth and metastasis by increasing BCSC self-renewal and may serve as a novel target for chemotherapy- and radiotherapy-resistant breast cancer.

Original languageEnglish (US)
Pages (from-to)3855-3866
Number of pages12
JournalCancer Research
Volume80
Issue number18
DOIs
StatePublished - Sep 15 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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