Double BRCA1 and BRCA2 inactivation is epistatic in mammary tumorigenesis and treatment response to PARP-inhibition and platinum drugs

Introduction BRCA1 and BRCA2 are the only two high-penetrance breast cancer susceptibility genes In addition to their well-known role in DNA double strand break repair. However, the implications for the tumor suppressor activity of BRCA1 and BRCA2 are incompletely understood.

Methods To investigate the distinct roles of BRCA1 and BRCA2 in breast cancer development and progression we generated transgenic mouse models harboring Brca1 and Brca2 Cre-recombinase mediated single or double knockout in the same mammary epithelial cell compartment.

Results We found that Brca1-deficient tumors (derived from K14cre;Brca1 ^F/F;Trp53 ^F/F mice), Brca2-deficient tumors (derived from K14cre;Brca2 ^F/F;Trp53 ^F/F mice), and Brca1 and Brca2 double-deficient tumors (derived from K14cre; Brca1 ^F/F;Brca2 ^F/F;Trp53 ^F/F mice) could not be discriminated in terms of tumor latency or histopathological pattern. Gene expression analysis revealed that Brca1-deficient and Brca2-deficient tumor show highly similar global gene expression profiles. Treatment of Brca1 and/or Brca2-deficient tumors with the PARP-inhibitor Olaparib and Cisplatin alone or in combination showed equal treatment response between the mouse models indication that a double mutation of Brca1 and Brca2 did not enhance sensitivity to Olaparib or Cisplatin.

Conclusion Our data suggests that Brca1 and Brca2 function are redundant in tumor suppressing and therapy response to PARP-inhibition and platinum drugs.