Abstract 4124: POPDC1 inhibits breast cancer cell migration and proliferation, and is regulated by EGFR (ErbB1) and cAMP

Abstract

Abstract Despite progress in the development of new treatments, breast cancer remains the second leading cause of global cancer morbidity and mortality (1). Identification and validation of effective therapeutic targets is thus essential for the development of better breast cancer treatments and improved prognoses. This project seeks to develop POPDC proteins as potential therapeutic targets for inhibiting breast cancer migration and proliferation. POPDC1 (also known as blood vessel epicardial substance or BVES), is a cAMP-binding transmembrane protein encoded by the POPDC1 gene. Loss or suppression of POPDC1 has been correlated with enhanced aggressive cancer cell behaviour (2-6). Suppression of POPDC1 promotes cell migration and invasion in hepatocellular carcinoma and tumourigenesis in colorectal cancer (2,4,5,7). Furthermore, we have previously shown that loss of POPDC1 promotes cell proliferation and migration in breast cancer and glioblastoma cells (3,8). Using a cAMP-agarose pulldown assay, we confirmed that POPDC1 interact with, and is upregulated by cAMP in luminal A (MCF7) and triple-negative (MDA231) breast cancer cells. Furthermore, immunocytochemistry and Western blotting has shown that POPDC1 expression is abrogated in MCF7 and MDA231 breast cancer cells compared to normal breast cells (HMepC). To confirm that POPDC1 negatively regulates migration and proliferation in breast cancer cells, we conducted knock-in experiments where overexpression of POPDC1 significantly inhibited cell migration and proliferation in MCF7 and MDA231 cells. Interestingly, epidermal growth factor receptor (EGFR/ErbB1) signalling negatively regulates POPDC1 expression in MCF7 and MDA231 cells and reduces the capacity of POPDC1 to inhibit cell migration. Epidermal growth factor reversed POPDC1-mediated inhibition of cell migration, an effect blocked by the AG 1478 (an EGFR inhibitor), suggesting EGFR-dependent modulation of POPDC1 activity. Furthermore, we have established for the first time using human breast tissue sections that Her2- status correlates with low POPDC1 expression while Her2+ status correlates with high POPDC1 expression. This suggests further interaction between EGF and POPDC1 and that any links between these molecules diverges at the level of the different EGFRs. Taken together, this strong dataset shows that POPDC1 plays a major role in breast cancer tumourigenesis that is at least in part, modulated by EGFR and cAMP signalling pathways. Indeed, these seem to demonstrate differential control of POPDC1 expression. This interplay and the fact that POPDC1 downregulation may be a downstream molecular target of the EGF cascade suggest that POPDC1 and its stabilisation may be a therapeutic strategy in the future of breast cancer. Citation Format: Johanna N. Amunjela, Steven J. Tucker. POPDC1 inhibits breast cancer cell migration and proliferation, and is regulated by EGFR (ErbB1) and cAMP [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4124. doi:10.1158/1538-7445.AM2017-4124