Abstract P6-20-10: Role of GPR110 in breast cancer

Abstract

Abstract Our long-term goal is to discover adhesion GPCR targets in breast cancer. Our previous studies have found GPR110 to be overexpressed in tumorigenic cell population as well as in anti-HER2 drug-resistant derivatives of HER2+ breast cancer cells. In subsequent studies, we found that GPR110 knockdown inhibited anchorage-independent cell growth, mammosphere formation, and invasion/migration of HER2+ breast cancer cells. Conversely, overexpression of GPR110 by lentiviral delivery of cDNA enhanced anchorage-independent cell growth, mammosphere formation, and invasion/migration in HER2+ breast cancer cells. In addition, GPR110 overexpression led to increase in the % of Aldefluor-positive tumorigenic cell population, further emphasizing the role of GPR110 as a mediator of tumorigenesis in addition to the metastatic processes in HER2+ breast cancer. Among various subtypes of breast cancer, GPR110 expression was higher in HER2+ and basal subtypes, most of which are triple-negative (negative for ER, PR, and HER2), compared to luminal A and B subtypes. GPR110 was either gene amplified or upregulated in 4% of all breast cancers based on the publicly available TCGA dataset. GPR110 overexpression predicted poorer recurrence-free survival in triple-negative breast cancer. Furthermore, GPR110 was overexpressed in brain metastatic lesions compared to mammary tumors in patient-derived xenograft models of triple-negative breast cancer (WHIM2 and WHIM30). Knocking down GPR110 reduced anchorage-dependent and -independent cell growth, mammosphere formation, and invasion/migration of triple-negative breast cancer cells. Overall, our results suggest that GPR110 may be a potential drug target in HER2+ and triple-negative breast cancer. Drug discovery efforts to identify GPR110 antagonists will provide useful pharmacological tools for validating GPR110 as a drug target in breast cancer. Since GPR110 is also overexpressed in various other types of cancer, understanding the mechanism of GPR110 upregulation and signaling in cancer is an important future direction. This work was supported by the Department of Defense Grants W81XWH-14-1-0340 and W81XWH-14-1-0341 to Drs. Trivedi and Schiff, respectively. Citation Format: Bhat R, Qin L, De Angelis C, Sahay D, Bhargava D, Creighton C, Yadav P, Yazdanfard S, Alrawi A, Yadav V, Vasaikar S, Nanda S, Sethunath V, Fu X, Zhang B, Narkar V, Schiff R, Trivedi M. Role of GPR110 in breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-10.