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

IRS-1 和 -2 信号在乳腺发育和癌症中的作用

• 批准号: 7904710
• 负责人: Adrian V Lee
• 金额: $ 30.13万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-15 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7904710
• 关键词: Acinus organ component; Adaptor Signaling Protein; Address; Affect; Binding; Biological Markers; Breast Diseases; Cell Polarity; Cells; Complex; Data; Development; Embryo; Epithelial Cells; Feedback; Funding; Gene Targeting; Genes; Goals; Growth; Histologic; Human; Hyperplasia; In Vitro; Insulin-Like-Growth Factor I Receptor; Knockout Mice; Lactation; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Measures; Mediating; Messenger RNA; Metabolism; Morphogenesis; Mus; Neoplasm Metastasis; Oncogenes; Outcome; Pathway interactions; Patients; Phenocopy; Premalignant; Receptor Signaling; Regulation; Role; Signal Transduction; Testing; Transgenic Mice; Translating; in vivo Model; inhibitor/antagonist; insulin receptor substrate 1 protein; malignant breast neoplasm; mammary gland development; migration; novel; outcome forecast; overexpression; public health relevance; receptor; response; tumor; tumor progression; tumorigenesis

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.

描述（由申请人提供）：胰岛素受体底物1和2（IRSS）是胰岛素样生长因子-I受体（IGF-IR）下游的大型适配器蛋白，可调节正常生长，代谢，生存和分化。最近的研究表明，IRS可以与许多肿瘤基因的转化能力相互作用，并且在功能上是必需的，而IRS在包括乳腺癌在内的许多人类肿瘤中升高和过度活跃。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，并确定它们是否可能在预测对抗IGF-IR抑制剂的反应中起作用。 为了更好地了解IRS在乳腺发育和乳腺癌中的作用，在上一个资金期间，我们创建并研究了IRS动作的几种新颖的体外和体内模型。使用IRS-NULL小鼠，我们发现IRS是胚胎乳腺芽形成和最大泌乳所必需的。使用人生的MCF-10A细胞，我们表明，IRSS的过表达通过改变极性，增殖和存活来破坏ACINI的形成。最后，我们用IRS-1或IRS-2的乳腺特异性过表达产生了转基因小鼠，两条小鼠都表现出渐进的乳腺增生，肿瘤和转移。有趣的是，其他使用IRS-2-NULL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如何调节乳腺细胞极性，转化和肿瘤发生？ 2）为什么IRS-1和IRS-2都会引起转化，而仅需要IRS-2的转移？ 3）IRSS在乳腺癌的进展和预后中是否重要，并且可以预测对抗IGF-IR抑制剂的反应水平和/或活性？我们将以以下特定目的解决这些问题：1）IRS-1和IRS-2是否通过APKC介导的极性复合物的破坏来破坏MCF-10A Acini的形态发生，并促进IGF-IR下游的增殖和生存？ 2）IRS-2是否利用NF-？B活性的唯一双向阳性调节来调节迁移，入侵和转移？ 3）IRS在乳腺癌的进展和预后中是否重要，并且可以用作对抗IGF-IR治疗的反应的预测指标吗？ 这些研究的长期影响将更好地理解IRS在乳腺癌中的作用，并且可能是预测对乳腺癌IGF-IR抑制剂反应的新生物标志物。 公共卫生相关性：这项研究的目的是更好地了解信号适配器（IRS）在乳腺癌中的作用。该研究将阐明IRS功能，然后将其转化为人类乳腺癌，以测试它们是否影响患者的预后并预测对抗IGF-IR抑制剂的反应。