Abstract 319: Role of GPR110 on tumorigenesis and metastasis in HER2+ breast cancer in the context of anti-HER2 drug resistance
Authors: Sahay Debashish , Bhat Raksha , Rimawi Motthafar , Osborne C. Kent , Schiff Rachel , Trivedi Meghana V. 
Published: July 2016

Abstract
Drug resistance is a major limitation of treatment regimens targeting the human epidermal growth factor receptor-2 (HER2) in breast cancers that overexpress this protein. Therefore, identification of novel drug targets to overcome anti-HER2 drug resistance is an unmet clinical need. Our previous studies have suggested that GPR110 may be a potential target for anti-HER2 drug resistance and tumorigenicity. Furthermore, GPR110 is an orphan receptor in the adhesion G-protein coupled receptor family, members of which have shown a role in cancer metastasis. In this study, our objectives were (1) to assess the gene expression of GPR110 using the Taqman RT-PCR assay in anti-HER2 drug resistant and in cancer stem-like cell population of various HER2+ breast cancer cell line models and (2) to investigate the effects of GPR110 gene knockdown on tumorigenesis and metastasis using various cell-based assays in HER2+ breast cancer cell lines and their anti-HER2-resistant derivatives. Cells transfected with non-targeting and 3 independent GPR110-targeting siRNAs were used to assess anchorage-independent cell growth, mammosphere formation, and cell invasion and migration. We found that GPR110 gene expression was significantly higher (&gt;/ = 2-fold) in lapatinib-resistant (LR), trastuzumab-resistant (TR), and lapatinib + trastuzumab-resistant (LTR) derivatives of BT474, SKBR3 and UACC812 cell lines compared to the parental cells. GPR110 gene expression was also significantly higher (&gt;/ = 1.9-fold) in ALDH+ versus ALDH- cell populations of BT474, SKBR3, MDA-MB-361 and HCC1569 cell lines. In addition, GPR110 gene knockdown led to a 55-85% (p&lt;0.05) decrease in anchorage-independent cell growth in BT474 and SKBR3 LTR derivatives but not in parental cells. A significant reduction in mammosphere count upon GPR110 knockdown was also seen in LTR derivatives (50-70%, p&lt;0.05) and not in parental BT474 cells. Interestingly, GPR110 knockdown in SKBR3 parental cells resulted in a significant reduction in cell invasion (40-50%, p&lt;0.05) and migration (40-50%, p&lt;0.05) suggesting a potential role of GPR110 in tumor cell dissemination. Overall, these results demonstrate that GPR110 is overexpressed in multiple anti-HER resistant derivatives as well as breast cancer stem-like cell population of various HER2+ breast cancer cell line models. Our studies also suggest a role of GPR110 in tumorigenesis specifically in the context of anti-HER2 drug resistance and in metastatic processes. Future in vivo studies will assess GPR110 as a novel drug target to overcome anti-HER2 drug resistance and combat metastasis in HER2+ breast cancer.
Citation Format: Debashish Sahay, Raksha Bhat, Motthafar Rimawi, C. Kent Osborne, Rachel Schiff, Meghana V. Trivedi. Role of GPR110 on tumorigenesis and metastasis in HER2+ breast cancer in the context of anti-HER2 drug resistance. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 319.