Investigating the Role of Endothelial BReast CAncer Susceptibility Gene 2 in Doxorubicin-induced Cardiotoxicity
Abstract
Doxorubicin (Dox) is a chemotherapeutic drug used to treat various malignancies including breast and ovarian cancers. Accumulating evidence implicates cardiac impairments associated with Dox treatment. The Breast Cancer Susceptibility Gene 2 (BRCA2) functions to maintain genome-wide stability by promoting DNA-damage repair. Accordingly, cardiomyocyte damage is specifically regulated by contributors of DNA damage repair such as BRCA2. The endothelium, the innermost cells of every blood vessel, act to protect our tissues from noxious elements, however, recent evidence suggests that BRCA2 knockdown compromises endothelial cell function. A putative role of endothelial BRCA2 during Dox-induced cardiotoxicity (DIC) remains unknown. We hypothesized that endothelial-specific loss of BRCA2 will induce endothelial dysfunction and exacerbate DIC. Our findings indicate that Dox treatment promoted weight loss and induced cardiomyocyte dysfunction in endothelial-specific BRCA2 knockdown mice in vivo, alongside profound endothelial dysfunction in vitro, and suggests a novel mechanism for DIC in the absence of BRCA2.