PPM1G promotes chemoresistance in triple negative breast cancer by enhancing YAP signaling

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with the poorest prognosis. The frequent development of chemoresistance is a major therapeutic challenge, yet the underlying mechanisms remain unclear. Here, we found that PPM1G was upregulated in TNBC, and high PPM1G expression was significantly correlated with poor prognosis in TNBC patients who received chemotherapy. Overexpression of PPM1G enhanced, whereas its knockdown suppressed, cancer stem cell-like properties and chemoresistance of TNBC both in vitro and in vivo . Mechanistic investigations revealed that PPM1G interacted with NDR1 and dephosphorylated it at Thr444, which in turn reduced the YAP phosphorylation level at Ser127, finally inducing YAP nuclear translocation and enhancing its transcriptional activity. Moreover, treatment with a YAP inhibitor Verteporfin significantly attenuated the PPM1G-induced chemoresistance both in vitro and in vivo . Overall, our study elucidated a role of the PPM1G/NDR1/YAP axis in TNBC chemoresistance. We proposed that PPM1G may serve as a predictive biomarker for the treatment response of TNBC to YAP inhibitor. ● PPM1G is upregulated in TNBC, and associated with poor prognosis in patients with TNBC who received chemotherapy. ● PPM1G promotes the cancer stem cell-like properties and chemoresistance of TNBC in vitro and in vivo. ● PPM1G interacts with NDR1 and directly dephosphorylates NDR1 at Thr444, which leads to a reduction in YAP phosphorylation (Ser127) and promotes the activation of YAP signaling. ● YAP inhibitor significantly attenuates the PPM1G-induced chemoresistance both in vitro and in vivo.