IRS function in breast cancer progression

IRS 在乳腺癌进展中的作用

• 批准号: 9899215
• 负责人: LESLIE M SHAW
• 金额: $ 38.32万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 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/9899215
• 关键词: Adaptor Signaling Protein; Address; Biological Response Modifier Therapy; Biology; Breast Cancer Patient; Breast Cancer Risk Factor; Breast cancer metastasis; C-terminal; Cancer Patient; Cause of Death; Cell physiology; Cells; Cytoplasmic Protein; Data; Data Set; Disease Progression; Family member; Frequencies; Gene Expression; Genes; 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; Pathway interactions; Play; Population; Primary Neoplasm; Property; Protein Isoforms; Proteins; RNA Splicing; Receptor Activation; Recurrent tumor; Regulation; Reporting; Resistance; Role; Signal Transduction; Stains; Tail; Testing; 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 cells; stemness; targeted treatment; tumor; tumor growth; tumor heterogeneity; tumor initiation; tumor progression

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.

本提案的总体目标是建立胰岛素受体底物-2（IRS 2） 促进乳腺癌转移。有待检验的新假设是IRS 2支持肿瘤细胞增殖。 乳腺癌干细胞（CSC）是乳腺癌的重要标志。CSC代表一个亚群 具有自我更新和产生肿瘤异质性能力的肿瘤细胞。这些细胞足以 引发原发性和复发性肿瘤生长以及继发性转移性肿瘤生长。了解 乳腺癌干细胞的生物学特性对于确定靶向这种侵袭性肿瘤细胞的新方法至关重要 人群，以有效地根除化疗耐药和转移性肿瘤。申请人的初步资料 建立IRS 2作为一个新的CSC基因，增强自我更新，他们确定了IRS 2内的一个结构域， 这一规定至关重要。IRS 2促进自我更新的能力也取决于其募集和 激活PI 3 K。IRS蛋白是胰岛素（IR）和胰岛素样生长的重要下游效应物 因子-1（IGF-1 R）受体。这两种受体都与癌症有关， 在某些癌症背景下，对CSC功能的调节进行了研究，对CSC功能的调节进行了严格分析 这些受体调节CSC功能的机制还没有得到解决。考虑到瞄准 IGF-1 R或IR直接可引起显著的代谢破坏，因此需要开发新的 抑制这些受体活性而不破坏其正常代谢调节的方法。的 申请人提出，选择性地破坏IRS 2的促进癌症进展的功能， 干扰其在正常代谢体内平衡中的作用将是这样一种方法。获得的结果 本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 与目前靶向CSC的疗法联合使用，以治疗耐药和转移性乳腺肿瘤。到 研究响应IR/IGF-1 R活化的IRS 2依赖性信号传导增强CSC的假设 自我更新和促进转移，申请人将：1）确定IRS 2而不是IRS 1有助于 乳腺CSC的功能。IRS 2在体内增强乳腺CSC功能的假设以及这种调节 2）阐明IRS 2调节乳腺癌转移的机制 CSC功能。IRS 2通过将因子募集到一个独特的 IRS 2 C-末端尾（SR）内的区域，与PI 3 K/AKT信号传导合作以调节CSC自我更新 研究IR/IGF-1 R信号通路在乳腺癌转移中的作用 CSCs的IRS 2依赖性调节。IR-A亚型优先启动IRS 2的假设 高胰岛素血症可增强该功能，从而促进肿瘤进展 将被审查。