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IRS function in breast cancer progression

IRS 在乳腺癌进展中的作用

基本信息

批准号：
10656330
负责人：
LESLIE M SHAW
金额：
$ 37.55万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10656330
关键词：
Adaptor Signaling Protein Address Biological Biology Breast Cancer Patient Breast Cancer Risk Factor Breast cancer metastasis C-terminal Cancer Patient Cause of Death Cells Chemoresistance Cytoplasmic Protein Data Data Set Disease Progression Family member Frequencies Gene Expression Goals Growth Homeostasis Hyperinsulinism Hypoxia IRS1 gene IRS2 gene Insulin Insulin Receptor Insulin-Like Growth Factor I Insulin-Like-Growth Factor I Receptor Maintenance Malignant Neoplasms Mammary Neoplasms Membrane Metabolic Metastatic breast cancer Mus Neoplasm Metastasis Outcome PI3K/AKT PIK3CG gene Pathway interactions Play Population Primary Neoplasm Property Protein Isoforms Proteins RNA Splicing Receptor Activation Recurrent Malignant Neoplasm Recurrent tumor Regulation Reporting Resistance Role Signal Transduction Stains Tail Testing Therapeutic Tumor Promotion Variant breast cancer progression breast cancer survival cancer recurrence cancer stem cell cancer subtypes experimental study human data in vivo malignant breast neoplasm neoplastic cell novel novel strategies novel therapeutics receptor recruit response self-renewal stem cell function stem cell genes stem cell self renewal stem cells stemness targeted treatment tumor tumor growth tumor heterogeneity tumor initiation tumor progression

项目摘要

The overall goal of this proposal is to establish the mechanism by which Insulin Receptor Substrate-2 (IRS2) promotes breast cancer metastasis. The novel hypothesis to be examined is that IRS2 supports tumor progression through its regulation of breast cancer stem cell (CSC) function. CSCs represent a sub-population of tumor cells that have the ability to self-renew and generate tumor heterogeneity. These cells are sufficient to initiate primary and recurrent tumor growth, as well as secondary metastatic tumor growth. Understanding the biology of breast CSCs is essential for identifying novel approaches to target this aggressive tumor cell population to effectively eradicate both chemoresistant and metastatic tumors. The applicant’s preliminary data establish IRS2 as a novel CSC gene that enhances self-renewal and they identify a domain within IRS2 that is essential for this regulation. The ability of IRS2 to promote self-renewal also depends upon its recruitment and activation of PI3K. The IRS proteins are essential downstream effectors of the insulin (IR) and insulin like growth factor-1 (IGF-1R) receptors. Both of these receptors have been implicated in cancer and although their involvement in regulating CSC function has been investigated in some cancer contexts, a rigorous analysis of the mechanisms by which these receptors regulate CSC function has not been addressed. Given that targeting either the IGF-1R or IR directly can cause significant metabolic disruption, there is a need to develop novel approaches to inhibit the activity of these receptors without disrupting their normal metabolic regulation. The applicant proposes that selectively disrupting functions of IRS2 that promote cancer progression without interfering with its role in normal metabolic homeostasis would be such an approach. The results obtained from the experiments outlined in this proposal will lay the groundwork for developing targeted approaches that could be used in combination with current therapies to target CSCs to treat resistant and metastatic breast tumors. To investigate the hypothesis that IRS2-dependent signaling in response to IR/IGF-1R activation enhances CSC self-renewal and promotes metastasis the applicant will: 1) Establish that IRS2 but not IRS1 contributes to the function of breast CSCs. The hypothesis that IRS2 enhances breast CSC function in vivo and that this regulation is essential for breast cancer metastasis will be examined; 2) Elucidate the mechanism by which IRS2 regulates CSC function. The hypothesis that IRS2 enhances CSC self-renewal by the recruitment of factor(s) to a unique region within the IRS2 C-terminal tail (SR) that cooperate with PI3K/AKT signaling to regulate CSC self-renewal and promote breast cancer metastasis will be examined; 3) Investigate the contribution of IR/IGF-1R signaling to IRS2-dependent regulation of CSCs. The hypothesis that the IR-A isoform preferentially initiates IRS2 signaling to promote stemness and this function is enhanced by hyperinsulinemia to promote tumor progression will be examined.

这项建议的总体目标是建立胰岛素受体底物-2(IRS2) 促进乳腺癌转移。需要检验的新假设是IRS2支持肿瘤通过其对乳腺癌干细胞(CSC)功能的调节而取得进展。CSC代表一个子群体具有自我更新能力并产生肿瘤异质性的肿瘤细胞。这些细胞足以启动原发和复发肿瘤生长，以及二次转移性肿瘤生长。了解乳腺CSCs的生物学对于确定靶向这种侵袭性肿瘤细胞的新方法至关重要。有效根除化疗耐药和转移性肿瘤。申请人的初步数据将IRS2建立为增强自我更新的新的CSC基因，并确定IRS2中的一个结构域，即对这项规定来说是必不可少的。IRS2促进自我更新的能力也取决于它的招募和激活PI3K。IRS蛋白是胰岛素(IR)和胰岛素样生长的重要下游效应因子 IGF-1R受体。这两种受体都与癌症有关，尽管它们的受体在一些癌症背景下，已经对参与调节CSC功能进行了调查，一项严格的分析这些受体调节CSC功能的机制还没有被解决。鉴于这一目标无论是IGF-1R还是IR都能直接引起显著的代谢紊乱，有必要开发新的在不破坏正常代谢调节的情况下抑制这些受体活性的方法。这个申请人提议选择性地干扰IRS2促进癌症进展的功能，而不是干扰其在正常代谢动态平衡中的作用将是这样一种方法。从以下方面获得的结果：该提案中概述的实验将为开发有针对性的方法奠定基础，这些方法可以与目前的治疗方法相结合，靶向CSCs治疗耐药和转移性乳腺肿瘤。至 IR/IGF-1R激活反应中IRS2依赖的信号增强CSC的假说自我更新和促进转移申请者将：1)确定IRS2而不是IRS1对乳腺干细胞的功能。IRS2在体内增强乳腺CSC功能的假说及其调节 2)阐明IRS2调控乳腺癌转移的机制 CSC功能。IRS2通过招募因子(S)来增强CSC自我更新的假说 IRS2 C末端尾部(SR)内与PI3K/AKT信号协同调节CSC自我更新的区域 3)研究IR/IGF-1R信号在乳腺癌转移中的作用对IRS2依赖的CSCs的调节。IR-A亚型优先启动IRS2的假说促进干性的信号和这一功能被高胰岛素血症增强以促进肿瘤进展将会被检查。