BRCA1 and BRCA2 are epistatic in mammary tumorigenesis and drug response

Introduction BRCA1 and BRCA2 are high-penetrance breast cancer susceptibility genes. When mutated, somatic loss of the second wild-type allel has been observed to cause cancer development leading to the assumption that BRCA1 and BRCA2 act as tumorsuppressor genes. 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 therapy response, we generated transgenic mouse models harboring Brca1 and Brca2 single or double knockout. We performed gene expression analysis and supervised classification, to compare gene expression profiles among mammary tumors derived from Brca1-, Brca2-, and Brca1/Brca2-deficient tumors and treated these tumors with a PARP inhibitor and platinum salts.

Results We found that Brca1-, Brca2-, and Brca1/Brca2-deficient tumors could not be discriminated in terms of tumor latency or histopathological pattern. Gene expression analysis revealed that Brca1-deficient and Brca2-deficient tumors have 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 an equal treatment response between the mouse models.

Conclusion Our data suggest that BRCA1 and BRCA2 genes have an equivalent role in tumorigenesis and therapy response by being functionally redundant.

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Artikel online veröffentlicht:
01. Juni 2021