Abstract C04: HGFL promotes the development and progression mammary tumors and represents an attractive therapeutic target

Abstract

Abstract A standard therapy for breast cancer is the use of receptor tyrosine kinase (RTK) inhibitors. RTKs efficiently target multiple receptors, including the Ron transmembrane receptor, whose activation leads to increased survival, migration, and angiogenesis through signaling pathways such as PI3K/Akt and NF-κB. Ron overexpression is correlated with increased metastasis and poor outcomes in patients. The only ligand for Ron is hepatocyte growth factor-like protein (HGFL), which is an endocrine factor secreted into the circulation from the liver. Published reports demonstrated that ectopic overexpression of HGFL in cancer cells leads to increased metastasis. However, no studies have examined the role of endogenous HGFL in Ron activation during tumor development and metastasis. We sought to test the hypothesis that HGFL is required for Ron receptor activation and mammary tumorigenesis. We utilized mice with mammary-specific Ron overexpression (MMTV-Ron), which develop mammary tumors with 100% incidence. MMTV-Ron mice were crossed to HGFL deficient (HGFL-/-) mice to generate MMTV-Ron X HGFL-/- mice. We compared mammary hyperplasia and tumor latency in MMTV-Ron mice with and without HGFL serially at 2.5, 4, 6, 8 and 10 months. Additional mice were followed to established tumor kinetics and growth and to examine metastatic dissemination. MMTV-Ron X HGFL-/- mice displayed decreased mammary hyperplasia and a significant delay in the time to tumor formation compared to control mice. Kinase assays show that Ron activation is reduced in mice with HGFL loss. Tumor cell proliferation was different between the groups while markers of apoptosis (TUNEL IHC and cleaved caspase 3 expression) were significantly increased in MMTV-Ron X HGFL-/- mice compared to controls. Western blot analysis of tumor lysates showed diminished activation of NF-κB signaling associated with HGFL loss. In conclusion, our data show that HGFL promotes the development of mammary hyperplasia and mammary tumor formation by enhancing tumor cell survival, Ron activation and NF-κB signaling. These data suggest that HGFL represents an excellent target for inhibiting Ron mediated tumor growth in human disease. Citation Format: Nancy M. Benight, Purnima Wagh, Susan E. Waltz. HGFL promotes the development and progression mammary tumors and represents an attractive therapeutic target. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C04.