FGFR in Mammary Gland Development and Breast Cancer

描述(申请人提供)：乳腺的发育是一个复杂的过程，由全身激素和局部生长因子共同调节。成纤维细胞生长因子家族的成员是本地产生的因子，参与了许多发育过程，包括乳腺、肺和前列腺的发育。间质中表达的FgflO和上皮中表达的FGFR2IIIb之间的旁分泌信号对肺和前列腺发育中的分支形态发生至关重要。因此，FGFR2IIIb信号对乳腺发育过程中导管形态发生的影响将通过分离的FGFR2IIIb-FGFR2IIIb小鼠乳腺上皮细胞来检测。在Cre介导的重组之后，细胞将被注射到透明的脂肪垫中，并将在突起中检查导管的发育。此外，将在罗森实验室产生的表达诱导性活性FGFR2(IFGFR2)的转基因小鼠中检验FGFR2信号在乳腺发育过程中的作用。为了进一步研究FGFR2在乳腺上皮细胞中的功能，将在细胞培养和iFGFR2转基因小鼠中检测FGFR结构的不同定位对信号通路持续时间和特异性的影响。这些研究的结果可能解释了在iFGFR2转基因小鼠中观察到的戏剧性表型，并将被用于设计改进的转基因小鼠模型，以进一步研究FGFR信号在乳腺发育和肿瘤发生中的作用。最后，基因阵列分析将被用来在转基因小鼠模型中识别在导管形态发生和肿瘤发展过程中受FGFR2激活调控的基因。这些研究应该识别新的FGFR调节基因，并有可能识别与乳腺癌病因学相关的基因。

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.