IGF and IGF Receptor Function in Mammary Development

描述（由申请方提供）：已证实IGF配体、IGF-I和IGF-II以及IGF I型受体（IGF-IR）在正常发育期间的乳腺上皮生长中发挥作用。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不同的表达。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，并显示了IGF-I在发育中的乳腺上皮和基质区室中表达的独特作用。我们进一步阐明了IGF-II表达的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的同源二聚体之外，IGF配体还可以通过IGF-IR和胰岛素受体（IR）的异源二聚体进行信号传导。我们的初步数据表明，乳腺特异性删除的IR在肺泡分化的结果在肺泡发育和泌乳的显着中断。此外，受体表达的分析表明，两个IR亚型的比例在乳腺上皮细胞在怀孕和哺乳期间变化，并且IGF-IR的显著部分作为与IR的混合受体存在于乳腺上皮细胞中。因此，本申请中提出的实验的目的是检验不同IGF信号传导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，我们提出了体外实验和体内转基因研究，以激活或破坏信号通过IR，IGF-IR和杂交受体在乳腺上皮细胞。 公共卫生相关性声明：实验结果将阐明IGF受体在正常乳腺上皮细胞增殖、存活和分化中的特异性作用和下游信号通路。这些研究也将对这些受体和途径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.