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

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 cm3. After euthanasia, Ca2+‐handling protein expression (Western blot) was evaluated. Exercise capacity was reduced in MMTV‐PyMT+ compared with MMTV‐PyMT− (Pinteraction=0.031). Longitudinal strain (Pgroup <0.001) and strain rate (Pgroup=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 (Pgroup=0.038) and end‐diastolic volume (Pgroup=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.

Keywords

• breast cancer
• Ca2+ handling
• cardiac function