Targeting the Ron-DEK Signaling Axis in Breast Cancer
Annual rept. 1 Sep 2013-31 Aug 2014
CHILDREN'S HOSPITAL CINCINNATI OH
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The Ron receptor tyrosine kinase is over-expressed and over-activated in a cohort of human cancers, with the most compelling data yet found in breast cancer. Specifically, Ron is overexpressed in approximately 50 of human breast cancers, and has been shown to be an independent predictor of both metastases and poor prognosis in women with this disease. While Ron overexpression appears to be an important factor in human breast cancer growth and metastasis, a significant gap exists in our knowledge about the signaling pathways that Ron activates in breast tumors, and about the importance of these pathways with respect to overall tumor growth and metastatic dissemination. Our laboratories have shown that mammary tumors from mice overexpressing Ron selectively in the mammary epithelium exhibit increased levels of the DEK proto-oncogene. In addition, we also show that ligand-induced Ron activation in human and murine breast cancer cell lines induces the accumulation of DEK protein. This accumulation of DEK is significant as DEK overexpression in breast cancer cell lines leads to increases in cell growth and migration while DEK depletion in breast cancer cells leads to dramatic reductions in cell growth and migration. Moreover, we also show that DEK deficient cells are more susceptible to DNA damage. Based on these data, our goal is to test the hypothesis that Ron-mediated DEK upregulation contributes functionally to breast cancer development, dissemination and resistance to clastogenic therapies and that targeting the Ron-DEK signaling axis may represent an important new therapeutic option for the treatment of breast cancer. To test this hypothesis, two Specific Aims were proposed. In Aim 1, we will determine the requirement of DEK in Ron overexpressing breast cancers utilizing a combination of DEK loss of function and Ron transgenic overexpression. Aim 2 will examine the therapeutic utility of targeting Ron and DEK on beta-catenin activation and breast cancer growth.
- Anatomy and Physiology
- Medicine and Medical Research