Insulin regulation of breast cancer stem cells

乳腺癌干细胞的胰岛素调节

• 批准号: 9797802
• 负责人: LESLIE M SHAW
• 金额: $ 16.75万
• 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: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9797802
• 关键词: Adaptor Signaling Protein; Breast Cancer Patient; Breast Cancer Risk Factor; Breast Cancer Treatment; C-terminal; Cell physiology; Cells; Clinical; Data; Data Set; Drug resistance; Epidemic; Gene Expression; Goals; Health; Homeostasis; Hyperinsulinism; IRS1 gene; IRS2 gene; Informal Social Control; Insulin; Insulin Receptor; Insulin Resistance; Insulin-Like-Growth Factor I Receptor; Lead; Maintenance; Malignant Neoplasms; Mammary Neoplasms; Mammospheres; Mediating; Metabolic; Modeling; Obesity; Outcome; PI3K/AKT; Pathway interactions; Play; Population; Primary Neoplasm; Protein Isoforms; RNA Splicing; Receptor Activation; Receptor Inhibition; Receptor Signaling; Recurrence; Recurrent tumor; Regulation; Reporting; Resistance; Risk; Role; Signal Pathway; Signal Transduction; Stem cells; Tail; Testing; Variant; cancer initiation; cancer recurrence; cancer risk; cancer stem cell; cancer therapy; experimental study; functional outcomes; genetic resistance; glucose uptake; in vivo; insulin signaling; malignant breast neoplasm; mouse model; neoplastic cell; new therapeutic target; novel; novel strategies; novel therapeutics; receptor; receptor expression; receptor function; recruit; response; self-renewal; side effect; stem cell population; stemness; targeted treatment; tumor; tumor growth; tumor heterogeneity; tumor initiation; tumor progression

Project Summary The overall goal of this proposal is to investigate the contribution of obesity to breast cancer initiation and progression by establishing the contribution of the insulin receptor (IR) signaling pathway to the regulation of breast cancer stem cells (CSCs). Obesity is a growing health epidemic that is associated with increased risk of both developing and dying from breast cancer. High insulin levels, which are a consequence of obesity, are an independent risk factor for breast cancer initiation and recurrence, which suggests a role for this signaling pathway in the regulation of breast CSCs. CSCs represent a sub-population of tumor cells that have the ability to self-renew and generate tumor heterogeneity and they are sufficient to initiate primary and recurrent tumor growth. Novel approaches are needed to target this aggressive tumor cell subpopulation. Although the involvement of the IR in regulating CSC function has been investigated in some cancer contexts, a rigorous analysis of the mechanism by which this receptor regulates CSC function has not been performed. This is clinically important because directly targeting the IR for cancer therapy is challenging given the essential role that this receptor plays in regulating normal metabolic homeostasis. The insulin receptor substrate (IRS) cytoplasmic adaptor proteins play key roles in the functional outcomes of IR signaling. In this proposal, the applicant advances the hypothesis that IRS2 mediates the regulation of breast CSCs by the IR, a function that cannot be executed by IRS1. The applicant’s preliminary data establish a role for IRS2 in the insulin-dependent regulation of CSC 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 applicant proposes that selectively disrupting functions of IRS2 that promote CSC self-renewal without interfering with its functions in normal metabolic homeostasis would be a novel approach for inhibiting IR regulation of CSCs. 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 primary and recurrent breast tumors. To investigate the hypothesis that IRS2-dependent signaling in response to IR activation enhances CSC self-renewal the applicant will: 1) Investigate insulin-dependent regulation of breast CSCs. The hypothesis that insulin signaling through IR-A/IRS2 regulates breast CSC self-renewal will be examined; 2) Determine the mechanism by which insulin signaling regulates breast CSC function. The hypothesis that IR signaling through IRS2 enhances CSC self-renewal through the recruitment of factor(s) to a unique region within the C-terminal tail of IRS2 (SR) that cooperate with PI3K/AKT signaling will be examined; 3) Elucidate the mechanism by which hyperinsulinemia promotes breast tumor growth. The hypothesis that IR/IRS2 regulation of CSCs is required for enhancing tumor growth in response to hyperinsulinemic conditions will be examined using both genetic and drug resistance models.

项目摘要 这项提案的总体目标是调查肥胖对乳腺癌发生的贡献， 通过建立胰岛素受体（IR）信号传导通路对胰岛素受体（IR）调节的贡献， 乳腺癌干细胞（CSCs）。肥胖症是一种日益严重的健康流行病， 她们都得了乳腺癌高胰岛素水平是肥胖的后果， 乳腺癌发生和复发的独立风险因素，这表明这种信号传导的作用 在乳腺癌干细胞的调节途径。CSC代表了肿瘤细胞的一个亚群， 自我更新和产生肿瘤异质性，它们足以启动原发性和复发性肿瘤 增长需要新的方法来靶向这种侵袭性肿瘤细胞亚群。虽然 IR参与调节CSC功能已经在一些癌症背景下进行了研究， 还没有对该受体调节CSC功能的机制进行分析。这是 临床上重要，因为直接靶向IR用于癌症治疗具有挑战性， 这种受体在调节正常代谢平衡中起着重要作用。胰岛素受体底物（IRS） 胞质衔接蛋白在IR信号传导的功能结果中起关键作用。在本提案中， 申请人提出了IRS 2通过IR介导乳腺CSC调节的假设，该功能 不能由IRS 1执行。申请人的初步数据确立了IRS 2在胰岛素依赖性糖尿病中的作用。 CSC自我更新的调节，他们确定了IRS 2内的一个域，这对该调节至关重要。的 IRS 2促进自我更新的能力也取决于其募集和激活PI 3 K。申请人 建议选择性地破坏IRS 2的功能，促进CSC自我更新，而不干扰其功能。 在正常代谢稳态中的功能将是抑制CSC的IR调节的新方法。 从本提案中概述的实验中获得的结果将为开发 靶向方法可与当前疗法结合使用，靶向CSC以治疗原发性 和复发性乳腺肿瘤。研究IR反应中的IRS 2依赖性信号转导的假说， 激活增强CSC自我更新申请人将：1）研究乳腺癌的胰岛素依赖性调节 CSC。胰岛素信号通过IR-A/IRS 2调节乳腺CSC自我更新的假设将是 2）确定胰岛素信号调节乳腺CSC功能的机制。的 假设IR信号通过IRS 2增强CSC自我更新，通过招募因子， 将检查IRS 2（SR）的C-末端尾部内与PI 3 K/AKT信号传导协作的独特区域; 3)阐明高胰岛素血症促进乳腺肿瘤生长的机制。的假设 CSC的IR/IRS 2调节是响应高胰岛素血症条件而增强肿瘤生长所必需的 将使用遗传和耐药性模型进行检查。