IGF and IGF Receptor Function in Mammary Development

本研究计划将阐明胰岛素样生长因子IGF-I和IGF- ii及其主要信号受体IGF-I型受体（IGF- ir）介导乳腺细胞生长和分化的机制。该提案的目的是验证以下假设：1)igf和IGF-IR对乳腺上皮细胞增殖和上皮间质信号传导至关重要；2)IGF-I和IGF-II在介导乳腺生长和分化方面具有不同的功能。本实验利用乳腺培养系统来确定IGF信号是否通过调节G1和G2检查点复合物的表达和激活来调节乳腺细胞周期进程。这些实验还将阐明乳腺发育过程中IGF/EGF相互作用介导细胞周期进程的机制。在第二个具体目标中，将使用遗传学方法在体外和体内测试IGF-IR信号在EGF或TGF-介导的乳腺生长中的作用。目的二的实验也将探讨IGF-IR在乳腺发育中上皮-基质信号传导中的作用。在研究计划的目标三中，我们将利用额外的遗传方法来测试IGF-I和IGF-II在乳腺发育中的功能是否存在差异。这些实验将包括确定乳腺中IGF-II表达是否直接受孕激素调节的研究。所产生的实验数据将对我们理解IGF和IGF受体在该组织正常发育中的功能产生重大影响。IGF和IGF- ir是越来越多的在正常乳房发育和乳腺癌中都有作用的基因之一，因此，这些实验的结果也将为理解IGF在乳腺癌中的作用机制提供基础。

The research plan outlined in this proposal will elucidate the mechanisms by which the insulin-like growth factors, IGF-I and IGF-II, and their primary signaling receptor, the IGF type I receptor (IGF-IR) mediate growth and differentiation of cells in the mammary gland. The goal of the proposal is to test the hypotheses that: 1) the IGFs and IGF-IR are essential for mammary epithelial proliferation and for epithelial-stromal signaling, and 2) IGF-I and IGF-II have differential functions in mediating mammary gland growth and differentiation. Experiments in specific aim one utilize a mammary gland culture system to determine whether IGF signaling regulates cell cycle progression in the mammary gland by regulating expression and activation of both the G1 and G2 checkpoint complexes. These experiments also will elucidate the mechanisms for IGF/EGF interactions in mediating cell cycle progression during mammary development. In the second specific aim, a genetic approach will be used to test the role of IGF-IR signaling in EGF or TGF- mediated growth of mammary glands in vitro and in vivo. Experiments in aim two also will address the role of the IGF-IR in epithelial-stromal signaling in mammary development. In aim three of the research plan, we will utilize additional genetic approaches to test whether IGF-I and IGF-II function differentially in mammary development. These experiments will include studies to determine whether IGF-II expression is directly regulated by progesterone in the mammary gland. The experimental data generated will have a significant impact on our understanding of IGF and IGF receptor function in normal development of this tissue. The IGFs and IGF-IR are among the increasing numbers of genes with proposed roles in both normal breast development and breast cancer, thus, results of these experiments also will provide a basis for understanding mechanisms of IGF action in breast cancer.