FGFR in Mammary Gland Development and Breast Cancer

FGFR 在乳腺发育和乳腺癌中的作用

• 批准号: 6551005
• 负责人: Kathryn L Schwertfeger
• 金额: $ 3.83万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-06 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6551005
• 关键词: apoptosis; biological transport; breast neoplasms; carcinogenesis; cell proliferation; fibroblast growth factor; gene expression; genetically modified animals; growth factor receptors; histogenesis; hormone regulation /control mechanism; laboratory mouse; mammary epithelium; mammary gland; microarray technology; neoplastic process; postdoctoral investigator; proteomics; terminal nick end labeling; tissue /cell culture

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.

描述（由申请人提供）：乳腺发育是一个复杂的过程，由全身激素和局部生长因子介导。成纤维细胞生长因子（Fgf）家族成员是局部产生的因子，参与许多发育过程，包括乳腺、肺和前列腺发育。在间充质中表达的FgflO和在上皮中表达的FGFR 2 IIIb之间的旁分泌信号传导对于肺和前列腺发育中的分支形态发生是关键的。因此，将使用从FGFR 2 IIIb-floxed小鼠分离的乳腺上皮细胞检查乳腺发育期间Fgf 10/FGFR 2 IIIb信号传导对导管形态发生的影响。在Cre介导的重组后，将细胞注射到清除的脂肪垫中，并在副产物中检查导管发育。此外，将在罗森实验室产生的表达诱导活性FGFR 2（iFGFR 2）的转基因小鼠中检查乳腺发育期间FGFR 2信号传导的影响。为了进一步检查乳腺上皮细胞中的FGFR 2功能，将在细胞培养物以及iFGFR 2转基因小鼠中检查FGFR构建体的差异定位对信号传导途径的持续时间和特异性的影响。这些研究的结果可以解释在iFGFR 2转基因小鼠中观察到的显著表型，并将用于设计改进的转基因小鼠模型，以进一步研究乳腺发育和肿瘤发生中的FGFR信号传导。最后，将利用基因阵列分析来鉴定在转基因小鼠模型中在导管形态发生和肿瘤发展期间受FGFR 2活化调节的基因。这些研究应该确定新的FGFR调控基因，并可能确定参与乳腺癌病因的基因。