IGF and IGF Receptor Function in Mammary Development

描述（由申请人提供）：IGF配体，IGF-I和IGF- ii，以及IGF I型受体（IGF- ir）在正常发育过程中在乳腺上皮的生长中发挥作用。此外，igf和IGF-IR促进乳腺癌细胞的增殖，并与乳腺癌的发生和生长有关。我们之前的研究表明，IGF-I和IGF-II在青春期和妊娠诱导的乳腺上皮发育过程中明显表达。在之前的资助期间，我们证明了IGF-I调节乳腺上皮细胞的细胞周期进程，并显示了IGF-I在发育中的乳腺上皮和间质室中表达的独特作用。我们进一步阐明了IGF-II的表达模式是如何在乳腺上皮中被调节的。最近的数据表明，除了IGF-IR的同型二聚体外，IGF配体还可以通过IGF-IR的异源二聚体和胰岛素受体（IR）发出信号。此外，一种被称为IR- a亚型的IR剪接变体对IGF-II具有高特异性，而对IGF-I没有特异性。我们的初步数据表明，在肺泡分化过程中，乳腺特异性的IR缺失会导致肺泡发育和泌乳的显著中断。此外，受体表达分析表明，在妊娠期和哺乳期乳腺上皮细胞中，两种IR亚型的比例有所不同，并且在乳腺上皮细胞中，有相当一部分IGF-IR作为IR的杂交受体存在。因此，本实验的目的是验证不同的IGF信号受体在肺泡分化和泌乳中具有不同功能的假设。为了验证这一假设，我们提出了通过体外实验和体内转基因研究来激活或破坏乳腺上皮细胞中IRs、IGF-IR和杂交受体的信号传导。

DESCRIPTION (provided by applicant): The IGF ligands, IGF-I and IGF-II, and the IGF type I receptor (IGF-IR) have demonstrated roles in growth of mammary epithelium during normal development. Moreover, the IGFs and IGF-IR promote proliferation of breast cancer cells and are implicated in incidence and growth of breast cancers. Our previous studies demonstrated that IGF-I and IGF-II are distinctly expressed during pubertal and pregnancy-induced development of the mammary epithelium. During the previous funding period, we demonstrated that IGF-I regulates cell cycle progression in mammary epithelial cells and showed unique roles for IGF-I expressed in epithelial and stromal compartments of the developing mammary gland. We further elucidated how patterning of IGF-II expression is regulated in the mammary epithelium. Recent data suggest that the IGF ligands can signal through heterodimers of the IGF-IR and the insulin receptor (IR) in addition to homodimers of the IGF-IR. Moreover, a splice variant of the IR known as the IR-A isoform, has high specificity for IGF-II but not IGF-I. Our preliminary data show that mammary specific deletion of the IR during alveolar differentiation results in significant disruption of alveolar development and lactation. Furthermore, analysis of receptor expression suggests that the ratio of the two IR isoforms varies in mammary epithelial cells during pregnancy and lactation and that a significant portion of the IGF-IR exists as a hybrid receptor with the IR in mammary epithelial cells. Thus, the goal of the experiments proposed in this application is to test the hypothesis that the different IGF signaling receptors have distinct functions in alveolar differentiation and lactation. To test this hypothesis, we propose both in vitro experiments and in vivo transgenic studies to activate or disrupt signaling through the IRs, IGF-IR and hybrid receptors in mammary epithelial cells. Public Health Relevance Statement: The results of the proposed experiments will elucidate IGF receptor-specific actions and downstream signaling pathways in proliferation, survival and differentiation of normal mammary epithelial cells. These studies will also have important implications for the roles of these receptors and pathways in breast cancers.