The Ron Receptor in Mammary Gland Biology

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DESCRIPTION (provided by applicant): 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 is an important factor in mammary gland tumorigenesis and metastasis; iii) Ron over-expression (or activation) in vivo can lead 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 and constitutive activation observed in human cancer by generating mouse models that mimic these 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.