Breast Cancer Promotes Cardiac Dysfunction Through Deregulation of Cardiomyocyte Ca2+-Handling Protein Expression That is Not Reversed by Exercise Training

Author(s):Show less -

da Costa, Tassia S. R. ^{[1, 2]} ; Urias, Ursula ^{[3, 1]} ; Negrao, V, Marcelo ; Jordao, Camila P. ^[1] ; Passos, Clevia S. ^[1] ; Gomes-Santos, Igor L. ^{[4, 1, 5]} ; Salemi, Vera Maria C. ^[1] ; Camargo, Anamaria A. ^[6] ; Brum, Patricia C. ^[3] ; Oliveira, Edilamar M. ^[3] ; Hajjar, Ludhmila A. ^{[1, 2]} ; Chammas, Roger ^[2] ; Filho, Roberto K. ^[1] ; Negrao, Carlos E. ^{[3, 1]}

Affiliation

^[1] Univ Sao Paulo, Heart Inst InCor Hosp Clin, Fac Med, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Canc Inst State Sao Paulo, Fac Med, Hosp Clin, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Sch Phys Educ & Sport, Sao Paulo - Brazil

^[4] Harvard Med Sch, Boston, MA 02115 - USA

^[5] Massachusetts Gen Hosp, Edwin L Steele Labs Tumor Biol, Dept Radiat Oncol, Boston, MA 02114 - USA

^[6] Hosp Sirio Libanes, Ctr Oncol Mol, Sao Paulo - Brazil

• Document type: Journal article
• Source: JOURNAL OF THE AMERICAN HEART ASSOCIATION; v. 10, n. 5 MAR 2 2021.
• Web of Science Citations: 1

Abstract

Background Patients treated for breast cancer have a high incidence of cardiovascular complications. In this study, we evaluated the impact of breast cancer on cardiac function and cardiomyocyte Ca2+-handling protein expression. We also investigated whether exercise training (ET) would prevent these potential alterations. Methods and Results Transgenic mice with spontaneous breast cancer (mouse mammary tumor virus-polyomavirus middle T antigen {[}MMTV-PyMT+], n=15) and littermate mice with no cancer (MMTV-PyMT-, n=14) were studied. For the ET analysis, MMTV-PyMT+ were divided into sedentary (n=10) and exercise-trained (n=12) groups. Cardiac function was evaluated by echocardiography with speckle-tracking imaging. Exercise tolerance test was conducted on a treadmill. Both studies were performed when the tumor became palpable and when it reached 1 cm(3). After euthanasia, Ca2+-handling protein expression (Western blot) was evaluated. Exercise capacity was reduced in MMTV-PyMT+ compared with MMTV-PyMT- (P-interaction=0.031). Longitudinal strain (P-group <0.001) and strain rate (P-group=0.030) were impaired. Cardiomyocyte phospholamban was increased (P=0.011), whereas phospho-phospholamban and sodium/calcium exchanger were decreased (P=0.038 and P=0.017, respectively) in MMTV-PyMT+. No significant difference in sarcoplasmic or endoplasmic reticulum calcium 2 ATPase (SERCA2a) was found. SERCA2a/phospholamban ratio was reduced (P=0.007). ET was not associated with increased exercise capacity. ET decreased left ventricular end-systolic diameter (P-group=0.038) and end-diastolic volume (P-group=0.026). Other morphological and functional cardiac parameters were not improved by ET in MMTV-PyMT+. ET did not improve cardiomyocyte Ca2+-handling protein expression. Conclusions Breast cancer is associated with decreased exercise capacity and subclinical left ventricular dysfunction in MMTV-PyMT+, which is at least partly associated with dysregulation of cardiomyocyte Ca2+ handling. ET did not prevent or reverse these changes. (AU)

• FAPESP's process: 15/22814-5 - Cancer and heart: new paradigms of diagnosis and treatment
• Grantee: Carlos Eduardo Negrão
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 15/19076-2 - Effect of physical exercise on the survival of circulating tumor cells and tumor formation
• Grantee: Clévia dos Santos Passos
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 14/13690-8 - Role of exercise training on prevention of cardiotoxicity provoked by doxorubicin
• Grantee: Igor Lucas Gomes dos Santos
• Support Opportunities: Scholarships in Brazil - Post-Doctoral