FGFR in Mammary Gland Development and Breast Cancer

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DESCRIPTION (provided by applicant): The development of the mammary gland is a complex process that is mediated by both systemic hormones and local growth factors. Members of the fibroblast growth factor (Fgf) family are locally produced factors that are involved in a number of developmental processes, including mammary gland, lung, and prostate development. Paracrine signaling between FgflO, which is expressed in the mesenchyme, and FGFR2IIIb, which is expressed in the epithelium, is critical for branching morphogenesis in lung and prostate development. Therefore, the effects of Fgf10/FGFR2IIIb signaling on ductal morphogenesis during mammary gland development will be examined using mammary epithelial cells isolated from FGFR2IIIb-floxed mice. Following Cre-mediated recombination, the cells will be injected into cleared fat pads and ductal development will be examined in the outgrowths. In addition, the effects of FGFR2 signaling during mammary gland development will be examined in transgenic mice generated in the Rosen laboratory that express an inducibly active FGFR2 (iFGFR2). To further examine FGFR2 function in mammary epithelial cells, the effects of differential localization of FGFR constructs on the duration and specificity of signaling pathways will be examined in cell culture as well as in the iFGFR2 transgenic mice. The results from these studies may explain the dramatic phenotypes observed in the iFGFR2 transgenic mice and will be used to design improved transgenic mouse models to further examine FGFR signaling in mammary gland development and tumorigenesis. Finally, gene array analysis will be utilized to identify genes that are regulated by FGFR2 activation in the transgenic mouse model during both ductal morphogenesis and tumor development. These studies should identify novel FGFR-regulated genes and potentially identify genes that are involved in the etiology of breast cancer.