P190-B RhoGAP regulates the microenvironment in the developing mammary gland

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DESCRIPTION (provided by applicant): My long-term career goal is to obtain a faculty position and to investigate the molecular pathways that regulate mammary gland (MG) development with the ultimate goal of determining how they are disrupted in breast cancer. My immediate goal is to develop an independent research program using new experimental approaches that will enhance my research skills. While a few of the objectives of this proposal are extensions of my postdoctoral studies, the majority are new lines of investigation on which I can build an independent research program. Dr. Rosen's laboratory and Baylor College of Medicine (BCM) have state-of-the-art technology, core laboratories, training programs, and a highly collaborative atmosphere with over 30 MG biologists/breast cancer researchers to facilitate success in my research. Thus, I believe that this is an ideal environment in which to pursue a career development award that will foster my transition to a faculty position. I generated inducible p190-B RhoGAP overexpressing mice to study the role of an essential signaling pathway in distinct stages of MG development and cancer. I showed that p190-B is required for MG morphogenesis and identified a novel role for p190-B in regulating the stromal-epithelial interactions that govern MG development. The aims of this proposal will investigate the signaling interactions by which p190-B regulates mammary epithelial cell (MEC) morphogenesis and the stromal-epithelial interactions that mediate MG development. To model MG morphogenesis in vitro, I will grow primary MECs and stromal cells isolated from the p190-B mice using a well-established 3D culture assay. This will allow me to dissect the complex cellular and molecular interactions by which p190-B regulates MG morphogenesis, which cannot be done in vivo. I will test the role of stromal cells in mediating the effects of p190-B on MG development in vivo, and microarray analysis will be performed on microdissected epithelium and stroma to determine the gene expression changes by which p190-B overexpression disrupts MG morphogenesis. It is now evident that the environment surrounding a breast tumor is disrupted, which facilitates tumor growth and spread. Understanding how the environment regulates MG development is a critical first step in determining how its disruption promotes breast cancer. The role of p190-B in human breast cancer is unknown. Because proteins like p190-B that are essential for development frequently become disrupted during tumorigenesis, p190-B may play an important role in breast cancer. An understanding of p190-B function in normal MG development is crucial if we are to determine how it is involved in breast cancer.