BRCA2 Protein Deficiency Exaggerates Doxorubicin-induced Cardiomyocyte Apoptosis and Cardiac Failure

Singh, Krishna K.; Shukla, Praphulla Chandra; Quan, Adrian; Desjardins, Jean-François; Lovren, Fina; Pan, Yi; Garg, Vinay; Gosal, Sumandeep; Garg, Ankit; Szmitko, Paul E.; Schneider, Michael; Parker, Thomas G.; Stanford, William L.; Leong‐Poi, Howard; Teoh, Hwee; Al‐Omran, Mohammed; Verma, Subodh

doi:10.1074/jbc.m111.292664

Cited by 48 publications

(32 citation statements)

References 48 publications

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“…In BRCA1/2-knockout mice, a higher susceptibility towards chemotherapy with anthracyclines (doxorubicin-induced) cardiotoxicity has been reported [23,24]. However, a prospective study in 39 BRCA1/2 mutation carriers compared to 42 sporadic breast cancer patients did not show an increased risk of anthracycline-induced cardiotoxicity in BRCA1/2 mutation carriers [65].…”

Section: Breast Cancer Treatment and Cardiovascular Risk In Brca1/2 Mmentioning

confidence: 87%

“…The cardioprotective role of BRCA genes has been suggested in BRCA1/2-knockout mice: BRCA genes protect cardiomyocytes from DNA damage, apoptosis and endothelial dysfunction and therefore function as gatekeepers of cardiac structure and function, while loss of BRCA1 in cardiomyocytes leads to a reduction in regulating cardiac energy supply, promoting endothelial cell apoptosis and reduces endothelial function [23][24][25].…”

Section: The Cardioprotective Role Of Brca Genesmentioning

confidence: 98%

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Cardiovascular risk of BRCA1/2 mutation carriers: A review

et al. 2016

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Section: Breast Cancer Treatment and Cardiovascular Risk In Brca1/2 Mmentioning

confidence: 87%

Section: The Cardioprotective Role Of Brca Genesmentioning

confidence: 98%

Cardiovascular risk of BRCA1/2 mutation carriers: A review

et al. 2016

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“…Twenty-nine % of women in Project HOPE also received left side radiation as part of their breast cancer treatment. The combined effects of cardiotoxic breast cancer treatment and primary aging in BRCA1/2+ women may be responsible for the above normal decline in yearly fitness capacity seen in the control group [38, 39]. Fleg et al report that between 40 and 50 years of age, the average % change in peak VO 2 for females over this decade is −10.9% [40].…”

Section: Discussionmentioning

confidence: 99%

Commercially available lifestyle modification program: randomized controlled trial addressing heart and bone health in BRCA1/2+ breast cancer survivors after risk-reducing salpingo-oophorectomy

et al. 2016

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Purpose The goal of this RCT was to examine the efficacy and safety of a web-based program to improve cardiovascular and bone health outcomes, among 35 BRCA1/2+ breast cancer survivors who underwent prophylactic oophorectomy and thus, experienced premature surgical menopause. Methods A 12-month commercially available web-based lifestyle modification program (Precision Nutrition Coaching) was utilized. Cardiovascular fitness, dietary intake, leisure-time activity, body composition, bone mineral density, bone structure, and muscle strength were assessed. Results Average adherence to all program components was 74.8%. Women in the intervention group maintained their cardiovascular fitness level over the 12 months (1.1 ± 7.9%), while the control group significantly decreased fitness capacity (−4.0 ± 7.5%). There was a significant difference between groups in percent change of whole body bone area (−0.8 ± 2.5 control and 0.5 ± 1.30 intervention). We also observed decreased BMI (−4.7 ± 6.2%) and fat mass (−8.6 ± 12.7%) in the intervention group due to significant concomitant decreases in caloric intake and increases in caloric expenditure. The control group demonstrated decreased caloric intake, and decreased lean tissue mass. Conclusions In this population at high risk for detrimental cardiovascular and bone outcomes, a commercially available lifestyle intervention program mitigated a decline in cardiovascular health, improved bone health, and decreased weight through fat loss. Implications for Cancer Survivors Precision Nutrition Coaching has shown benefit in breast cancer survivors for reduced risk of deleterious cardiovascular and bone outcomes.

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“…Finally, alterations in pathways that respond directly to DNA damage have been studied in the context of anthracyclineinduced myocyte toxicity. These studies indicate the following: 1) deficiency in poly(ADP-ribose) polymerase, an enzyme that repairs DNA single strand breaks, results in protection against doxorubicin-induced damage (123) and 2) deficiency in breast cancer susceptibility gene-2 protein, a tumor suppressor protein, results in exaggerated cardiomyocyte apoptosis and cardiac failure in mouse models of anthracycline exposure (114). These observations highlight the overall importance of cellular DNA repair mechanisms in the response to anthracycline exposure.…”

Section: Cell-specific Myocardial Response To Anthracyclinesmentioning

confidence: 99%

The tell-tale heart: molecular and cellular responses to childhood anthracycline exposure

Lindsey

Lange

Parsons

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Since the modern era of cancer chemotherapy that began in the mid-1940s, survival rates for children afflicted with cancer have steadily improved from 10% to current rates that approach 80% (60). Unfortunately, many long-term survivors of pediatric cancer develop chemotherapy-related health effects; 25% are afflicted with a severe or life-threatening medical condition, with cardiovascular disease being a primary risk (96). Childhood cancer survivors have markedly elevated incidences of stroke, congestive heart failure (CHF), coronary artery disease, and valvular disease (96). Their cardiac mortality is 8.2 times higher than expected (93). Anthracyclines are a key component of most curative chemotherapeutic regimens used in pediatric cancer, and approximately half of all childhood cancer patients are exposed to them (78). Numerous epidemiologic and observational studies have linked childhood anthracycline exposure to an increased risk of developing cardiomyopathy and CHF, often decades after treatment. The acute toxic effects of anthracyclines on cardiomyocytes are well described; however, myocardial tissue is comprised of additional resident cell types, and events occurring in the cardiomyocyte do not fully explain the pathological processes leading to late cardiomyopathy and CHF. This review will summarize the current literature regarding the cellular and molecular responses to anthracyclines, with an important emphasis on nonmyocyte cardiac cell types as well as those that mediate the myocardial injury response.

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BRCA2 Protein Deficiency Exaggerates Doxorubicin-induced Cardiomyocyte Apoptosis and Cardiac Failure

Cited by 48 publications

References 48 publications

Cardiovascular risk of BRCA1/2 mutation carriers: A review

Cardiovascular risk of BRCA1/2 mutation carriers: A review

Commercially available lifestyle modification program: randomized controlled trial addressing heart and bone health in BRCA1/2+ breast cancer survivors after risk-reducing salpingo-oophorectomy

The tell-tale heart: molecular and cellular responses to childhood anthracycline exposure

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