IRS-1 and -2 signaling in mammary development and cancer

描述(申请人提供)：胰岛素受体底物1和2(IRS)是胰岛素样生长因子-I受体(IGF-IR)下游的大接头蛋白，调节正常的生长、代谢、存活和分化。最近的研究表明，IRSS可以与许多癌基因相互作用，并且在功能上是许多癌基因转化所必需的，并且IRSS在包括乳腺癌在内的许多人类肿瘤中都升高和过度活跃。这些研究的长期目标是了解inuslin受体底物(IRs)在乳腺癌中的作用，并确定它们是否在预测抗IGF-IR抑制剂的反应中发挥作用。 为了更好地了解IRS在乳腺发育和乳腺癌中的作用，在上一个资助阶段，我们创建并研究了几个新的IRS体外和体内作用模型。使用IRS缺失的小鼠，我们发现IRSS是胚胎乳芽形成和最大哺乳所必需的。利用人类永生化的MCF-10A细胞，我们发现IRSS的过表达通过改变极性、增殖和存活来扰乱腺泡形成。最后，我们产生了乳腺特异性过表达IRS-1或IRS-2的转基因小鼠，这两个品系的小鼠都表现出进行性乳腺增生、肿瘤和转移。有趣的是，其他人使用IRS-2缺失小鼠的研究表明，乳腺肿瘤转移只需要IRS-2。 这些研究提出了三个基本问题：1)IRS如何调节乳腺细胞的极性、转化和肿瘤的发生？2)为什么IRS-1和IRS-2都能引起转化，而转移只需要IRS-2？3)IRS在乳腺癌的进展和预后中是否重要，以及IRS的水平和/或活性能否预测对抗IGF-IR抑制剂的反应？1)IRS-1和IRS-2是否都通过PKC介导的极性复合体破坏MCF-10A腺泡的形态发生，并促进IGF-IR下游的增殖和存活？2)IRS-2是否利用对核因子-B活性的独特双向正向调节来调节迁移、侵袭和转移？3)IRS-2在乳腺癌的进展和预后中是否重要，它们能否作为抗IGF-IR治疗反应的预测因子？ 这些研究的长期影响将是更好地了解IRS在乳腺癌中的作用，并可能成为预测IGF-IR抑制剂在乳腺癌中的反应的新的生物标志物。 公共卫生相关性：这项研究的目标是更好地了解信号转接器(IRS)在乳腺癌中的作用。这项研究将阐明IRS的功能，然后将其转化为人类乳腺癌，以测试它们是否会影响患者的预后，并预测对抗IGF-IR抑制剂的反应。

DESCRIPTION (provided by applicant): Insulin receptor substrates 1 and 2 (IRSs) are large adaptor proteins downstream of insulin-like growth factor-I receptor (IGF-IR) which modulate normal growth, metabolism, survival, and differentiation. Recent studies have shown that IRSs can interact with, and are functionally required for the transforming ability of many oncogenes, and IRSs are elevated and hyperactive in many human tumors including breast cancer. The long-term goal of these studies is to understand the role of inuslin receptor substrates (IRSs) in breast cancer, and determine if they may have a role in predicting response to anti-IGF-IR inhibitors. To better understand the role of IRSs in mammary gland development and breast cancer, in the last funding period, we created and studied several novel in vitro and in vivo models of IRS action. Using IRS-null mice we found that IRSs are required for embryonic mammary bud formation and for maximal lactation. Using human immortalized MCF-10A cells we showed that overexpression of IRSs disrupted formation of acini by altering polarity, proliferation, and survival. Finally, we generated transgenic mice with mammary-specific overexpression of either IRS-1 or IRS-2 with both lines of mice displaying progressive mammary hyperplasia, tumors, and metastasis. Intriguingly, studies from others using IRS-2-null mice have shown that only IRS-2 is required for mammary tumor metastasis. These studies have raised three fundamental questions: 1) How do IRSs modulate mammary cell polarity, transformation, and tumorigenesis? 2) Why do both IRS-1 and IRS-2 cause transformation, but only IRS-2 is required for metastasis? 3) Are IRSs important in breast cancer progression and prognosis, and can levels and/or activity predict response to anti-IGF-IR inhibitors? We will address these questions with the following specific aims: 1) Do both IRS-1 and IRS-2 disrupt morphogenesis of MCF-10A acini via aPKC mediated disruption of the polarity complex, and promote proliferation and survival downstream of IGF-IR? 2) Does IRS-2 utilize a unique bi-directional positive regulation of NF-?B activity to modulate migration, invasion, and metastasis? 3) Are IRSs important in breast cancer progression and prognosis, and can they be used as predictors of response to anti-IGF-IR therapy? The long-term impact of these studies will be a better understanidng of IRS action in breast cancer, and a possible new biomarker for predicting response to IGF-IR inhibitors in breast cancer. PUBLIC HEALTH RELEVANCE: The goal of this study is to better understand the role of signaling adaptors (IRSs) in breast cancer. The study will elucidate IRS function, and then translate this into human breast cancer to test if they affect patient prognosis and predict response to anti-IGF-IR inhibitors.