title: BRCA2 protein deficiency exaggerates doxorubicin-induced cardiomyocyte apoptosis and cardiac failure.
abstract: The tumor suppressor breast cancer susceptibility gene 2 (BRCA2) plays an important role in the repair of DNA damage, and loss of BRCA2 predisposes carriers to breast and ovarian cancers. Doxorubicin (DOX) remains the cornerstone of chemotherapy in such individuals. However, it is often associated with cardiac failure, which once manifests carries a poor prognosis. Because BRCA2 regulates genome-wide stability and facilitates DNA damage repair, we hypothesized that loss of BRCA2 may increase susceptibility to DOX-induced cardiac failure. To this aim, we generated cardiomyocyte-specific BRCA2 knock-out (CM-BRCA2(-/-)) mice using the Cre-loxP technology and evaluated their basal and post-DOX treatment phenotypes. Although CM-BRCA2(-/-) mice exhibited no basal cardiac phenotype, DOX treatment resulted in markedly greater cardiac dysfunction and mortality in CM-BRCA2(-/-) mice compared with control mice. Apoptosis in left ventricular (LV) sections from CM-BRCA2(-/-) mice compared with that in corresponding sections from wild-type (WT) littermate controls was also significantly enhanced after DOX treatment. Microscopic examination of LV sections from DOX-treated CM-BRCA2(-/-) mice revealed a greater number of DNA double-stranded breaks and the absence of RAD51 focus formation, an essential marker of double-stranded break repair. The levels of p53 and the p53-related proapoptotic proteins p53-up-regulated modulator of apoptosis (PUMA) and Bax were significantly increased in samples from CM-BRCA2(-/-) mice. This corresponded with increased Bax to Bcl-2 ratios and elevated cytochrome c release in the LV sections of DOX-treated CM-BRCA2(-/-) mice. Taken together, these data suggest a critical and previously unrecognized role of BRCA2 as a gatekeeper of DOX-induced cardiomyocyte apoptosis and susceptibility to overt cardiac failure. Pharmacogenomic studies evaluating cardiac function in BRCA2 mutation carriers treated with doxorubicin are encouraged.
authors.affiliation: Division of Cardiac Surgery, The Keenan Research Centre in the Li Ka Shing Knowledge Institute of St.Michael’s Hospital,Toronto, Ontario M5B 1W8, Canada.
authors.forename: Krishna K
authors.initials: KK
authors.lastname: Singh
authors.forename: Praphulla C
authors.initials: PC
authors.lastname: Shukla
authors.forename: Adrian
authors.initials: A
authors.lastname: Quan
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Desjardins
authors.forename: Fina
authors.initials: F
authors.lastname: Lovren
authors.forename: Yi
authors.initials: Y
authors.lastname: Pan
authors.forename: Vinay
authors.initials: V
authors.lastname: Garg
authors.forename: Sumandeep
authors.initials: S
authors.lastname: Gosal
authors.forename: Ankit
authors.initials: A
authors.lastname: Garg
authors.forename: Paul E
authors.initials: PE
authors.lastname: Szmitko
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schneider
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Parker
authors.forename: William L
authors.initials: WL
authors.lastname: Stanford
authors.forename: Howard
authors.initials: H
authors.lastname: Leong-Poi
authors.forename: Hwee
authors.initials: H
authors.lastname: Teoh
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Omran
authors.forename: Subodh
authors.initials: S
authors.lastname: Verma
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D024682:BRCA2 Protein / Q000172:deficiency / Q000235:genetics*; D004317:Doxorubicin / Q000633:toxicity*; D006333:Heart Failure / Q000139:chemically induced* / Q000453:epidemiology / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology*; D010641:Phenotype; D012307:Risk Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D000903:Antibiotics, Antineoplastic; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin