Abstract 2826: Expression of HBEGF enhances breast carcinoma cell motility, invasion and metastasis.

Abstract

Abstract Despite advances in screening and prevention, breast cancer is still associated with a high mortality rate that predominantly results from the development of metastatic disease. One of the key steps of the metastatic cascade is invasion. Previous work in our lab has discovered a paracrine loop between tumor cells and macrophages in which tumor cells are capable of stimulating macrophages through the secretion of CSF-1 and the tumor associated macrophages in turn aid in tumor cell invasion by secreting EGF. The goal of our project is to explore how expression of EGFR ligands, specifically HBEGF, by tumor cells affects the paracrine loop, invasion and metastasis. Previous studies have shown that HBEGF is often found to be coexpressed with the EGFR and that HBEGF expression in tumors is correlated with more biologically aggressive disease and poorer patient prognosis. An initial Oncomine cancer gene expression analysis showed that HBEGF expression was correlated with more rapid recurrence of disease in breast cancer upon removal of the primary breast tumor. Based on the published data, we decided to focus our study on this particular ligand. Using MTLn3 rat mammary adenocarcinoma cells and human MDA-MB 231 breast adenocarcimona cells that were transduced to overexpress HBEGF, we have shown that HBEGF expression enhanced tumor cell invasion by increasing tumor cell motility, invadopodium formation and matrix degradation. We have also discovered that expression of HBEGF enhanced metastasis by making tumor cell invasion independent of the paracrine loop. Our studies suggest that for tumors that express HBEGF, therapies that target tumor associated macrophages using CSF-1R inhibitors may not be effective in inhibiting tumor cell invasion. In addition, we have found that HBEGF expression causes an increase in the recruitment of tumor associated macrophages and tumor angiogenesis along with increased expression of VEGF, which suggests that anti-VEGF treatment could be particularly useful for treating patients whose tumors overexpress HBEGF. Citation Format: Zhen Ni Zhou, Ved P. Sharma, Brian T. Beaty, Paraic Kenny, H. Stephen Wiley, John S. Condeelis, Jeffrey E. Segall. Expression of HBEGF enhances breast carcinoma cell motility, invasion and metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2826. doi:10.1158/1538-7445.AM2013-2826