Abstract
Despite heightened risk of cardiotoxicity associated with combination therapy of anthracyclines and trastuzumab in HER2-positive breast cancer patients, little research effort has been invested in exploring the molecular mechanisms of cardiotoxicity induced by this combination therapy. In this study, we demonstrate that trastuzumab downregulates both gene and protein expressions of type IIB DNA topoisomerase/DNA topoisomerase IIB (TOP2B), a major intracellular target mediating doxorubicin-induced cardiotoxicity, in human primary cardiomyocytes. This in turn induces DNA damage activity and DNA double strand breaks, which is indicated by the enhanced phosphorylation of H2AX (γH2AX) and ataxia telangiectasia and Rad3-related protein (ATR pS428) in trastuzumab-treated cardiomyocytes. Furthermore, concurrent or sequential treatment of doxorubicin and trastuzumab significantly increases the downregulation of the protein levels of TOP2B, enhances apoptosis and cell growth inhibition, and promotes production of reactive oxidative and nitrative species in human cardiomyocytes as compared to either trastuzumab or doxorubicin treatment, indicating augmentation of cardiotoxicity in combination therapy. Additionally, our data reveal that doxorubicin treatment increases the levels of ErbB2/HER2 expression in human cardiomyocytes as compared with that in cells not treated with doxorubicin, leading to the enhanced activity downstream of HER2 signaling. Consequently, this may render the cardiomyocytes to become addicted to HER2 signaling for survival under stressed conditions. Enhanced HER2 protein expression leaves cardiomyocytes more sensitive to trastuzumab treatment after doxorubicin exposure. This study provides molecular basis for significantly increased cardiotoxicity in cancer patients who are treated with anthracyclines and trastuzumab-based combination regimens.
Highlights
Chemotherapy followed by trastuzumab in adjuvant setting is the standard of care for the treatment of patients with ErbB2/human epidermal growth factor receptor 2 (HER2)-positive breast cancers [1,2,3]
Because TOP2B has been previously discovered as a major target responsible for the cardiotoxicity induced by doxorubicin [24], it is intuitive that trastuzumab enhances doxorubicin’s toxic effect to heart by rendering further inhibition of TOP2B in cardiomyocytes via either concurrent or sequential treatment
We find that doxorubicin treatment enhances the levels of HER2 expression and upregulates downstream of HER2 signaling in cardiomyocytes
Summary
Chemotherapy followed by trastuzumab in adjuvant setting is the standard of care for the treatment of patients with ErbB2/HER2-positive breast cancers [1,2,3]. A retrospective study, which evaluated the incidence of cardiac abnormalities in HER2positive cancer patients receiving adjuvant trastuzumab concluded that approximately 1 in 4 women might develop left ventricular systolic dysfunctions after treatment with trastuzumab in adjuvant settings [5]. Despite the improved patient inclusion and exclusion criteria, concurrent and sequential therapy regimens consisting www.impactjournals.com/oncotarget of anthracyclines and trastuzumab continue to cause significant cardiotoxicity in succeeding clinical studies. A recent clinical study with 18,540 young adult women showed that the estimated cumulative incidence of major cardiac events was 6.6% for the anthracycline-trastuzumab sequential therapy, 5.1% for trastuzumab without anthracyclines, 2.0% for anthracyclines without trastuzumab, and 3.2% for other chemotherapy over 3 years [7]. This study concluded that patients receiving sequential therapy have higher risk of developing hospital-based cardiac dysfunctions compare with patients receiving anthracycline alone [7]
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