TY - JOUR
T1 - RAD51AP1 deficiency reduces tumor growth by targeting stem cell self-renewal
AU - Bridges, Allison Elaine
AU - Ramachandran, Sabarish
AU - Pathania, Rajneesh
AU - Parwal, Utkarsh
AU - Lester, Adrienne
AU - Rajpurohit, Pragya
AU - Morera, Daley S.
AU - Patel, Nikhil
AU - Singh, Nagendra
AU - Korkaya, Hasan
AU - Manicassamy, Santhakumar
AU - Prasad, Puttur D.
AU - Lokeshwar, Vinata B
AU - Lokeshwar, Balakrishna L
AU - Ganapathy, Vadivel
AU - Thangaraju, Muthusamy
N1 - Funding Information:
B.L. Lokeshwar reports grants from U.S. Veterans Administration (grant no. 5I01BX003862-02) during the conduct of the study. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
We thank Penny P. Roon, Donna Kumiski, and Dr. Brendan Marshall in the Electron Microscopy and Histology core facility, Augusta University Cancer Center, for their help in histologic analysis. This work was supported by Augusta University Intramural PSRP Pilot Award (IGPP00004), Start-up, and Bridge funding (to M. Thangaraju).
PY - 2020/9/15
Y1 - 2020/9/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-19-3713
DO - 10.1158/0008-5472.CAN-19-3713
M3 - Article
C2 - 32665355
SN - 0008-5472
VL - 80
SP - 3855
EP - 3866
JO - Cancer Research
JF - Cancer Research
IS - 18
ER -