Abstract A16: The α-arrestin ARRDC3 functions as a metastasis suppressor by regulating GPCR activation of the Hippo pathway

Abstract

Abstract G protein-coupled receptors (GPCRs) are key regulators of the Hippo pathway, a well-established mediator of tumorigenesis and cancer progression. The Hippo pathway is a promising therapeutic target, yet developing inhibitors for the core pathway components has proven difficult. As critical regulators of the Hippo pathway, GPCRs represent a potential upstream therapeutic target for cancer. However, despite the success and promise of GPCRs as therapeutic targets, there are currently no FDA-approved drugs targeting GPCRs for cancer. Protease-activated receptor-1 (PAR1) is a GPCR that has been shown to activate the Hippo pathway and also promote breast cancer progression. PAR1 is overexpressed in breast cancer patient tissue biopsies and in breast carcinoma cell lines and correlates with increased rates of metastasis and poor prognosis and increased invasion and metastatic potential, respectively. One mechanism that leads to PAR1 aberrant overexpression is defective lysosomal trafficking and degradation of the receptor, leading to persistent signaling. We recently showed that arrestin domain containing protein-3 (ARRDC3), an adaptor protein for E3 ubiquitin ligases, functions as a tumor suppressor by controlling proper PAR1 trafficking and degradation in highly aggressive, triple-negative breast carcinoma cells. The dysregulation of PAR1 trafficking due to loss of ARRDC3 expression leads to persistent signaling and promotes breast cancer invasion. However, the mechanism by which ARRDC3 specifically regulates PAR1-stimulated Hippo signaling to promote breast cancer metastasis remains unknown. Here, we show that ARRDC3 regulates GPCR activation of the Hippo pathway in basal-like breast cancer, where the transcriptional coactivators YAP and TAZ play differential roles in GPCR-mediated signaling and invasive capacity. ARRDC3 re-expression in invasive breast carcinoma cells attenuates PAR1-mediated activation of the Hippo pathway through regulation of TAZ but not YAP activation. Furthermore, siRNA knockdown of TAZ inhibits PAR1-stimulated Hippo signaling and invasion, whereas YAP siRNA knockdown has no effect. Our studies suggest a crucial role for ARRDC3 and TAZ in PAR1-Hippo pathway signaling in breast carcinoma invasion and metastasis. A better 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. Citation Format: Aleena K.S. Arakaki, Wen-An Pan, Helen Wedegaertner, JoAnn Trejo. The α-arrestin ARRDC3 functions as a metastasis suppressor by regulating GPCR activation of the Hippo pathway [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr A16.