Insulin regulation of breast cancer stem cells

乳腺癌干细胞的胰岛素调节

• 批准号: 10227661
• 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/10227661
• 关键词: Adaptor Signaling Protein; Breast Cancer Patient; Breast Cancer Risk Factor; Breast Cancer Treatment; C-terminal; 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; 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 regulation; 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 function; stem cell genes; stem cell population; stem cell self renewal; 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 该提案的总体目标是调查肥胖对乳腺癌倡议的贡献和 通过建立胰岛素受体（IR）信号通路对调节的贡献的进展 乳腺癌干细胞（CSC）。肥胖是一种日益增长的健康流行病，与增加的风险有关 从乳腺癌发育和死亡。高胰岛素水平是肥胖的结果，是 乳腺癌开始和复发的独立危险因素，这表明该信号的作用 乳房CSC调节的途径。 CSC代表具有能力的肿瘤细胞的亚群 自我更新和产生肿瘤异质性，并且足以启动原发性和复发性肿瘤 生长。需要采用新的方法来瞄准这种侵略性肿瘤细胞亚群。虽然 在某些癌症的情况下已经研究了IR参与调节CSC功能的参与，这是严格的 尚未执行该接收器调节CSC函数的机制的分析。这是 临床上重要 该受体可以控制正常的代谢稳态。胰岛素受体底物（IRS） 细胞质适配器蛋白在IR信号的功能结果中起关键作用。在此提案中， 申请人推进了IRS2介导IR调节乳房CSC的假设，这一功能是 IRS1不能执行。申请人的初步数据在胰岛素依赖性中确定了IRS2的作用 CSC自我更新的调节，并确定IRS2内的域，这对于该调节至关重要。 IRS2促进自我更新的能力也取决于其PI3K的募集和激活。申请人 有选择地破坏IRS2功能的建议，这些功能促进CSC自我更新而不会干扰其 正常代谢稳态中的功能将是抑制IR调节CSC的一种新方法。 从本提案中概述的实验中获得的结果将为开发奠定基础 可以与当前疗法结合使用以靶向CSC来治疗初级的靶向方法 和复发性乳腺肿瘤。研究以下假设：IRS2依赖性信号响应于IR 激活增强了CSC自我更新的申请人将：1）研究乳腺胰岛素依赖性调节 CSC。通过IR-A/IRS2信号调节乳房CSC自我更新的假设是 检查； 2）确定胰岛素信号传导调节乳腺CSC功能的机制。这 假设通过IRS2信号传导通过募集因子募集到A增强CSC自我更新 将检查与PI3K/AKT信号坐标的IRS2（SR）C末端尾部内的独特区域； 3）阐明高胰岛素血症促进乳腺肿瘤生长的机制。假设是 IR/IRS2调节CSC是对高胰岛素条件的响应增强肿瘤生长所必需的 将使用遗传和耐药模型对其进行检查。