The Agonist of JWA Gene JAC1 Suppresses Proliferation of Breast Cancer Through the JWA/p38/SMURF1/HER2 Signaling

Background: The overexpression of HER2 is associated with malignant proliferation and invasiveness in breast cancer. Although HER2-targeting drugs have been clinically applied for cancer treatment, none of them could reduce overexpressed HER2. In this study, we reported that JAC1 could suppress proliferation of breast cancer cells via degrading HER2. Methods JWA-HER2 association was analyzed by IHC in 90 paired cases of breast cancer and adjacent non-cancerous tissues. Regulatory effect of JAC1, the agonist of JWA gene, on HER2-positive breast cancer cells was studied using colony formation assay. The effect of JAC1 on the localization of HER2 was detected by immunofluorescence microscopy assay. Western blotting, RT-PCR and immunoprecipitation assay were utilized to investigate the mechanisms of JWA on regulating HER2. Finally, xenograft mouse models were established in nude mice using BT474 cells to confirm the effect of JAC1 in vivo . Results JAC1, a small molecule agonist of JWA gene, dose-dependently suppressed proliferation in HER2-positive breast cancer in vitro and in vivo through degrading HER2. The mechanistic evidences showed that JAC1 increased the ubiquitination of HER2 at the K716 through the E3 ubiquitin ligase SMURF1. Furthermore, SMURF1 was activated due to reduced expression of NEDD4, an E3 ubiquitin ligase for SMURF1 through the JWA-p38-GATA-1-NEDD4 axis. Conclusions JAC1 suppresses the proliferation in HER2-positive breast cancer through the JWA/p38/GATA-1/NEDD4/SMURF1/HER2 signaling. JAC1 may serve as a novel therapeutic agent to breast cancer.