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Different Mechanisms in Doxorubicin-induced Cardiomyopathy: Impact of BRCA1 and BRCA2 Mutations
Version 1
: Received: 28 December 2023 / Approved: 28 December 2023 / Online: 28 December 2023 (05:10:03 CET)
A peer-reviewed article of this Preprint also exists.
Nguyen, H.C.; Frisbee, J.C.; Singh, K.K. Different Mechanisms in Doxorubicin-Induced Cardiomyopathy: Impact of BRCA1 and BRCA2 Mutations. Hearts 2024, 5, 54-74. Nguyen, H.C.; Frisbee, J.C.; Singh, K.K. Different Mechanisms in Doxorubicin-Induced Cardiomyopathy: Impact of BRCA1 and BRCA2 Mutations. Hearts 2024, 5, 54-74.
Abstract
Germline mutations in Breast cancer susceptibility gene 1 and 2 (BRCA1 and BRCA2) cause breast, ovarian and other cancers, and the chemotherapeutic drug doxorubicin (Dox) is widely used to treat these cancers. However, Dox use is limited by latent induction of severe cardiotoxicity known as Dox-induced cardiomyopathy, for which there are no specific treatments currently available. Dox is administered into the systemic circulation, where it readily translocates into sub-cellular compartments, and disrupts the integrity of DNA. Accumulating evidence indicates that oxidative stress, DNA damage, inflammation and apoptosis all play a central role in Dox-induced cardiomyopathy. The BRCA1 and BRCA2 proteins are distinct as they perform crucial yet separate roles in the homologous recombination repair of DNA double-strand breaks, thereby maintaining genomic integrity. Additionally, both BRCA1 and BRCA2 mitigate oxidative stress and apoptosis in both cardiomyocytes and endothelial cells. Accordingly, BRCA1 and BRCA2 are essential regulators of pathways that are central to the development of cardiomyopathy induced by Doxorubicin. Despite extensive investigations, there exists a gap in knowledge about the role of BRCA1 and BRCA2 in Doxorubicin-induced cardiomyopathy. Here, we review the previous findings and associations about the expected role and associated mechanisms of BRCA1 and 2 in Dox-induced cardiomyopathy and future perspectives.
Keywords
BRCA2; BRCA1; doxorubicin; breast cancer; heart failure
Subject
Medicine and Pharmacology, Cardiac and Cardiovascular Systems
Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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