Abstract 5066: Matriptase mediated signaling in breast cancer.

Abstract

Abstract Historically proteases have been associated with tumor progression and metastasis through degradation of the basement membrane. In recent years these enzymes have also been shown to play key roles in the activation of growth factors and cytokines, thereby activating pro-oncogenic signaling pathways. Matriptase is an epithelia-specific pericellular protease which has received considerable attention recently spurred by its consistent dysregulation in human epithelial tumors including breast cancer. Several institutions are currently developing small and large molecule inhibitors of matriptase, however thus far no studies have been published focusing on the role of matriptase in breast cancer growth and progression. Presently we do not know whether matriptase plays a causal or promotional role in breast carcinogenesis and therefore its potential as an anti-cancer drug target is still unexplored. In the following study we will perform both functional and mechanistic studies of matriptase in breast cancer using parallel, complementary in-vitro and in-vivo genetic “loss-of-function” strategies. Matriptase efficiently cleaves pro-hepatocyte growth factor (pro-HGF) into active HGF, the cognate ligand of the proto-oncogene tyrosine kinase receptor c-Met, and thereby elicits pro-tumorigenic downstream signaling events. Both c-Met and matriptase are expressed on the surface of mammary epithelial cells and breast carcinoma cells, whereas the c-Met ligand and matriptase proteolytic target pro-HGF is secreted by stromal fibroblasts thus defining a paracrine growth factor activation and signaling mechanism. Our goal with this project is to determine whether matriptase is a novel target which could provide an opportunity for developing improved breast cancer intervention drugs in the future. Citation Format: Gina L. Zoratti, Christopher Bergum, Julie L. Boerner, Karin List. Matriptase mediated signaling in breast cancer. [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 5066. doi:10.1158/1538-7445.AM2013-5066