Regulation of GPCR activation of the Hippo pathway in metastatic breast cancer

Abstract

G protein‐coupled receptors (GPCRs) regulate the Hippo signaling pathway, a developmental pathway involved in tumorigenesis and metastasis. Although GPCRs promote cancer progression and are highly druggable, there are currently no FDA‐approved drugs targeting GPCRs for cancer treatment. Protease‐activated receptor‐1 (PAR1) is a GPCR that both activates the Hippo pathway and promotes breast cancer progression. PAR1 is overexpressed in breast cancer patient tumor biopsies and in invasive breast carcinoma cell lines, and correlates with increased metastasis and poor prognosis. We found that PAR1 overexpression is due to defective lysosomal trafficking and results in persistent signaling observed in multiple triple‐negative breast carcinoma cell lines including the model invasive MDA‐MB‐231 cells. We recently showed that the α‐arrestin domain containing protein‐3 (ARRDC3), a tumor suppressor, is reduced or lost in highly aggressive triple‐negative breast carcinoma and this is responsible for aberrant PAR1 lysosomal trafficking and persistent signaling, leading to increased invasion. However, the link between ARRDC3 expression and PAR1‐stimulated Hippo pathway regulation in invasive breast cancer is not known and was examined. Here, we show that ARRDC3 regulates GPCR activation of the Hippo pathway in triple‐negative breast cancer, where the transcriptional co‐activators YAP and TAZ display distinct functions. ARRDC3 re‐expression in invasive breast carcinoma cells attenuates GPCR‐stimulated Hippo signaling and invasion that is mediated by activation of TAZ but not YAP. Furthermore, siRNA‐targeted depletion of TAZ, but not YAP inhibits GPCR‐induced Hippo signaling and invasion. An understanding of the mechanisms by which the Hippo pathway is regulated by GPCRs may lead to new potential therapeutic targets for the treatment or prevention of metastatic breast cancer.Support or Funding InformationFunding for this project was provided by the HHMI Gilliam Fellowship for Advanced Study, the UCSD Graduate Training Program in Cellular and Molecular Pharmacology through NIH General Medical Sciences, T32 GM007752 and the UCSD Tribal Membership Initiative (Aleena Arakaki) and by the National Institute of Health NIGMS R01 GM090689 and R35 GM127121 (JoAnn Trejo).