The long-term objective of my research is to define the in vivo role of the receptor tyrosine kinase Ron in mammary gland biology. Virtually nothing is known regarding the function of Ron in the breast. However, recent studies have shown that Ron is over-expressed and highly phosphorylated in a large number of human and feline breast cancers. In order to define the in vivo significance of this receptor, my laboratory generated mice with a targeted ablation of the tyrosine kinase (TK) domain of Ron. Preliminary analysis of breast development in these mice lacking Ron signaling has pointed to a major, and largely unappreciated, role for the receptor tyrosine kinase Ron in mammary gland biology. Our preliminary studies indicate that Ron is required for the normal growth control of the mammary gland both during development and during tumorigenesis. The studies in this proposal are aimed at examining in greater detail, the role of this relatively unknown receptor in mammary development and tumorigenesis. The proposed studies will take the initial steps toward defining the underlying mechanism by which Ron influences mammary gland development and tumor biology in vivo. Our goal is to rigorously explore the following specific hypotheses: i) Ron is an influential determinant in mammary gland development; ii) Ron signaling augments mammary gland tumorigenesis and metastasis; and iii) Ron over-expression in vivo leads to mammary transformation. In order to test these hypotheses, we have proposed three Specific Aims.
Aim I is to define the contribution of Ron signaling in mammary gland development by localizing the sites of Ron synthesis and Ron action (stromal, epithelial or systemic).
Aim II is to use a genetic approach to examine the in vivo impact of Ron signaling in the pathogenesis of oncogene-induced mammary gland tumors. For this aim we will analyze the role of Ron signaling and activation in mammary tumor formation and metastatic dissemination.
In Aim III we will focus on understanding the role of Ron over-expression observed in human cancer by generating mouse models that mimic this conditions. In total, we hope to understand the role of a potentially important and unknown receptor in mammary biology with the hopes of ultimately impacting the treatment of human breast cancer. ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Metabolic Pathology Study Section (MEP)
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Woodhouse, Elizabeth
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University of Cincinnati
Schools of Medicine
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Zhao, H; Chen, M-S; Lo, Y-H et al. (2014) The Ron receptor tyrosine kinase activates c-Abl to promote cell proliferation through tyrosine phosphorylation of PCNA in breast cancer. Oncogene 33:1429-37
Eyob, Henok; Ekiz, Huseyin Atakan; Derose, Yoko S et al. (2013) Inhibition of ron kinase blocks conversion of micrometastases to overt metastases by boosting antitumor immunity. Cancer Discov 3:751-60
Gray, Jerilyn K; Paluch, Andrew M; Stuart, William D et al. (2012) Ron receptor overexpression in the murine prostate induces prostate intraepithelial neoplasia. Cancer Lett 314:92-101
Marshall, Aaron M; McClaine, Rebecca J; Gurusamy, Devikala et al. (2012) Estrogen receptor alpha deletion enhances the metastatic phenotype of Ron overexpressing mammary tumors in mice. Mol Cancer 11:2
Wagh, Purnima K; Zinser, Glendon M; Gray, Jerilyn K et al. (2012) Conditional deletion of ?-catenin in mammary epithelial cells of Ron receptor, Mst1r, overexpressing mice alters mammary tumorigenesis. Endocrinology 153:2735-46
Wagh, P K; Gray, J K; Zinser, G M et al. (2011) ?-Catenin is required for Ron receptor-induced mammary tumorigenesis. Oncogene 30:3694-704
Privette Vinnedge, L M; McClaine, R; Wagh, P K et al. (2011) The human DEK oncogene stimulates ?-catenin signaling, invasion and mammosphere formation in breast cancer. Oncogene 30:2741-52
Welsh, JoEllen; Zinser, Lindsay N; Mianecki-Morton, Laurel et al. (2011) Age-related changes in the epithelial and stromal compartments of the mammary gland in normocalcemic mice lacking the vitamin D3 receptor. PLoS One 6:e16479
Logan-Collins, Jocelyn; Thomas, Ryan M; Yu, Peter et al. (2010) Silencing of RON receptor signaling promotes apoptosis and gemcitabine sensitivity in pancreatic cancers. Cancer Res 70:1130-40
Jiang, Pingping; Hu, Qiuping; Ito, Mitsuhiro et al. (2010) Key roles for MED1 LxxLL motifs in pubertal mammary gland development and luminal-cell differentiation. Proc Natl Acad Sci U S A 107:6765-70

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