Tumor Suppressor Alpha‐arrestin ARRDC3 Controls GPCR Signaling and Breast Cancer Invasion

Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor prognosis and lacks druggable targets. The development of chemotherapy resistance substantially accounts for the high recurrence and death of TNBC patients. Therefore, understanding how TNBC acquires chemoresistance will provide an opportunity to identify new target therapies. G protein‐coupled receptors (GPCR) are the largest family of FDA‐approved drugs but remain overlooked in cancer therapy. Substantial evidence indicates that dysregulated GPCR signaling drives cancer initiation and progression, this is particularly relevant for protease‐activated receptor‐1 (PAR1). However, how PAR1 signaling is dysregulated and confers chemoresistance in aggressive cancers is poorly understood. Arrestin‐domain containing protein 3 (ARRDC3) is a newly identified tumor suppressor in breast cancer and its expression is lost or suppressed in the basal‐like breast cancers, which constitutes the majority of TNBC. Whether and how ARRDC3 play a role in PAR1 signaling and impacts chemoresistance of breast cancer is unclear. The study objective is to address the link between the ARRDC3 and PAR1 signaling and breast cancer chemoresistance. PAR1 is a promising drug target for breast cancer and its expression is correlated with high tumor grade and poor prognosis in breast cancer patients. PAR1 is irreversibly activated by thrombin and its overexpression is sufficient to promote neoplastic transformation and essential for breast cancer metastasis in vitro and in vivo . In invasive breast carcinomas, PAR1 signals constitutively due to a defect in lysosomal trafficking and promotes invasiveness. We hypothesize that ARRDC3 represses PAR1 signaling and chemoresistance in TNBC cells. In this study, we used a lentiviral based ARRDC3 doxycycline‐inducible (pSLIK‐ARRDC3) system in TNBC lines to examine the role and mechanism by which ARRDC3 and PAR1 signaling contribute to chemoresistance. Here we report that ARRDC3 and PAR1 expression are inversely correlated in luminal versus basal‐like invasive breast carcinoma and in patient tissue samples. Activation of PAR1 promotes chemoresistance, while ARRDC3 expression re‐sensitizes cells response to chemotherapy agents. Mechanistically, ARRDC3 specifically represses the magnitude of endosomal PAR1‐induced p38 mitogen‐activated protein kinases (MAPK) signaling but has no effect on extracellular signal‐regulated kinase‐1,2 (ERK1,2) in pSLIK‐ARRDC3 MDA‐MB‐231 cells. In conclusion, our study suggests that PAR1 may be a therapeutic target for attenuation of chemoresistance in ARRDC3‐deficient TNBC patients. Support or Funding Information This work is funded by NIH R01 GM090689‐05 and UC Tobacco‐related Disease Research Program High Impact Pilot Award 26IP‐0050 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .