IGF and IGF Receptor Function in Mammary Development

描述(申请人提供)：IGF配体，IGF-I和IGF-II，以及IGF-I型受体(IGF-IR)已被证明在正常发育的乳腺上皮生长中起作用。此外，IGFS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。我们以前的研究表明，IGF-I和IGF-II在青春期和妊娠诱导的乳腺上皮发育过程中有明显的表达。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，并证明了IGF-I在发育中的乳腺上皮和间质中表达的独特作用。我们进一步阐明了IGF-II的表达模式是如何在乳腺上皮中调节的。最近的数据表明，除了IGF-IR的同源二聚体外，IGF配体还可以通过IGF-IR和胰岛素受体(IR)的异源二聚体来传递信号。此外，IR的一个剪接变体被称为IR-A亚型，对IGF-II有高度的特异性，但对IGF-I没有。我们的初步数据显示，在肺泡分化过程中，乳腺特异的IR缺失会导致明显的肺泡发育和哺乳中断。此外，对受体表达的分析表明，在妊娠和哺乳期间，两种IR亚型在乳腺上皮细胞中的比例不同，很大一部分IGF-IR以杂交受体的形式存在于乳腺上皮细胞中。因此，在本申请中提出的实验的目的是检验不同的IGF信号受体在肺泡分化和哺乳中具有不同功能的假设。为了验证这一假设，我们提出了体外实验和体内转基因研究，以激活或破坏乳腺上皮细胞中IRS、IGF-IR和混合受体的信号传递。 公共卫生相关声明：拟议的实验结果将阐明IGF受体在正常乳腺上皮细胞增殖、存活和分化中的特定作用和下游信号通路。这些研究还将对这些受体和通路在乳腺癌中的作用产生重要影响。

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.