At the Intersection of Cardiology and Oncology: TGFβ as a Clinically Translatable Therapy for TNBC Treatment and as a Major Regulator of Post-Chemotherapy Cardiomyopathy

Abstract

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that accounts for the majority of breast cancer-related deaths due to the lack of specific targets for effective treatments. While there is immense focus on the development of novel therapies for TNBC treatment, a persistent and critical issue is the rate of heart failure and cardiomyopathy, which is a leading cause of mortality and morbidity amongst cancer survivors. In this review, we highlight mechanisms of post-chemotherapeutic cardiotoxicity exposure, evaluate how this is assessed clinically and highlight the transforming growth factor-beta family (TGF-β) pathway and its significance as a mediator of cardiomyopathy. We also highlight recent findings demonstrating TGF-β inhibition as a potent method to prevent cardiac remodeling, fibrosis and cardiomyopathy. We describe how dysregulation of the TGF-β pathway is associated with negative patient outcomes across 32 types of cancer, including TNBC. We then highlight how TGF-β modulation may be a potent method to target mesenchymal (CD44⁺/CD24^-) and epithelial (ALDH^high) cancer stem cell (CSC) populations in TNBC models. CSCs are associated with tumorigenesis, metastasis, relapse, resistance and diminished patient prognosis; however, due to plasticity and differential regulation, these populations remain difficult to target and continue to present a major barrier to successful therapy. TGF-β inhibition represents an intersection of two fields: cardiology and oncology. Through the inhibition of cardiomyopathy, cardiac damage and heart failure may be prevented, and through CSC targeting, patient prognoses may be improved. Together, both approaches, if successfully implemented, would target the two greatest causes of cancer-related morbidity in patients and potentially lead to a breakthrough therapy.

Keywords: CSC; TNBC TGF-β; cardiology; oncology.

Figure 1

Overview of Conventional TGF-β Signaling. A schematic overview of conventional (SMAD-mediated) TGF-β signaling occurring after TGF-β ligand binding which leads to the activation of TGF-β type I and TGF-β type II receptor heteromeric complexes which can induce the phosphorylation of SMAD2 and 3, promoting complex formation with co-SMAD (SMAD4). This trimeric complex can translocate into the nucleus and induce the transcription of numerous genes, including those involved in cardiac remodeling and fibrosis, as well as cellular differentiation, survival, invasion and apoptosis.

Figure 2

Database analysis of patients with TGF-β-altered/unaltered gene expression and survival. Kaplan–Meier curves for progression-free survival of the patients with alterations in TGF-β signaling in cancer samples (red curve) in comparison with patients with unaltered expression (blue curve). n = 10,610, *** p = 9.99 × 10⁻¹⁰, log-rank test.