Clinically Translatable Approaches of Inhibiting TGF-beta to Target Cancer Stem Cells in TNBC

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that disproportionally accounts for the majority of breast cancer-related deaths due to the lack of specific targets for effective treatments. In this review, we highlight the complexity of the transforming growth factor-beta family (TGF-beta) pathway and discuss how the dysregulation of the TGF-beta pathway promotes oncogenic attributes in TNBC, which negatively affects patient prognosis. Moreover, we discuss recent findings highlighting TGF-beta inhibition as a potent method to target mesenchymal (CD44(+)/CD24(-)) and epithelial (ALDH(high)) cancer stem cell (CSC) populations. CSCs are associated with tumorigenesis, metastasis, relapse, resistance, and diminished patient prognosis; however, due to differential signal pathway enrichment and plasticity, these populations remain difficult to target and persist as a major barrier barring successful therapy. This review highlights the importance of TGF-beta as a driver of chemoresistance, radioresistance and reduced patient prognosis in breast cancer and highlights novel treatment strategies which modulate TGF-beta, impede cancer progression and reduce the rate of resistance generation via targeting the CSC populations in TNBC and thus reducing tumorigenicity. Potential TGF-beta inhibitors targeting based on clinical trials are summarized for further investigation, which may lead to the development of novel therapies to improve TNBC patient prognosis.

Automated summary

This article examines the complexity of the TGF-β pathway and its role in promoting oncogenic properties in TNBC, while also pointing out the significance of CSCs in breast cancer tumorigenesis, metastasis, relapse, resistance, and patient prognosis.