PDGFRa and b Play Critical Roles in Mediating Foxq1-Driven Breast Cancer Stemness and Chemoresistance

Many epithelial–mesenchymal transition (EMT)–promoting transcription factors have been implicated in tumorigenesis and metastasis as well as chemoresistance of cancer. However, the underlying mechanisms mediating these processes are unclear. Here, we report that Foxq1, a forkhead box-containing transcription factor and EMT-inducing gene, promotes stemness traits and chemoresistance in mammary epithelial cells. Using an expression profiling assay, we identified Twist1, Zeb2, and PDGFRa and b as Foxq1 downstream targets. We further show that PDGFRa and b can be directly regulated by Foxq1 or indirectly regulated through the Foxq1/Twist1 axis. Knockdown of both PDGFRa and b results in more significant effects on reversing Foxq1-promoted oncogenesis in vitro and in vivo than knockdownof either PDGFRa or b alone. In addition, PDGFRb is a more potent mediator of Foxq1-promoted stemness traits than PDGFRa. Finally, pharmacologic inhibition or gene silencing of PDGFRs sensitizes mammary epithelial cells to chemotherapeutic agents in vitro and in vivo. These findings collectively implicate PDGFRs as critical mediators of breast cancer oncogenesis and chemoresistance driven by Foxq1,with potential implications for developing novel therapeutic combinations to treat breast cancer. Cancer Res; 75(3);