The FOXC2 Transcription Factor: A Master Regulator of Chemoresistance in Cancer

FOXC2, a member of the forkhead box family of transcription factors, is an emerging oncogene that has been linked to several hallmarks of cancer progression. Among its many oncogenic functions is the promotion of drug resistance, with evidence supporting roles for FOXC2 in escape from broad classes of chemotherapeutics across an array of cancer types. In this Mini-Review, we highlight the current understanding of the mechanisms by which FOXC2 drives cancer chemoresistance, including its roles in the promotion of epithelial-mesenchymal transition, induction of multidrug transporters, activation of the oxidative stress response, and deregulation of cell survival signaling pathways. We discuss the clinical implications of these findings, including strategies for modulating FOXC2-associated chemoresistance in cancer. Particular attention is given to ways in which FOXC2 and its downstream gene products and pathways can be targeted to restore chemosensitivity in cancer cells. In addition, the utility of FOXC2 expression as a predictor of patient response to chemotherapy is also highlighted, with emphasis on the value of FOXC2 as a novel biomarker that can be used to guide therapeutic choice towards regimens most likely to achieve clinical benefit during frontline therapy.

Automated summary

FOXC2 is an emerging oncogene that is associated with several hallmarks of cancer progression. It plays an important role in promoting drug resistance and has been shown to be involved in escape from broad classes of chemotherapeutics across different cancer types. This Mini-Review provides an overview of the mechanisms by which FOXC2 drives cancer chemoresistance, including its roles in promoting epithelial-mesenchymal transition, inducing multidrug transporters, activating the oxidative stress response, and deregulating cell survival signaling pathways. The clinical implications of these findings and strategies for modulating FOXC2-associated chemoresistance in cancer are discussed, with a focus on targeting FOXC2 and its downstream gene products and pathways to restore chemosensitivity in cancer cells. The utility of FOXC2 expression as a predictor of patient response to chemotherapy is also highlighted, emphasizing its value as a novel biomarker that can guide therapeutic choice in frontline therapy.