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.

该提案的总体目标是建立胰岛素受体底物-2（IRS2）的机制 促进乳腺癌转移。要研究的新假设是IRS2支持肿瘤 通过调节乳腺癌干细胞（CSC）功能的进展。 CSC代表子人群 具有自我更新和产生肿瘤异质性的能力的肿瘤细胞的。这些细胞足以 启动原发性和复发性肿瘤生长以及继发转移性肿瘤生长。了解 乳腺CSC的生物学对于识别靶向这种侵略性肿瘤细胞的新方法至关重要 种群有效地放射化学抗性和转移性肿瘤。申请人的初步数据 将IRS2建立为一种新型CSC基因，可以增强自我更新，并确定IRS2中的域 对于此法规至关重要。 IRS2促进自我更新的能力也取决于其招聘和 PI3K的激活。 IRS蛋白是胰岛素（IR）和胰岛素类似生长的基本下游作用 因子1（IGF-1R）受体。这两个受体都暗示了癌症，尽管它们的 在某些癌症情况下研究了参与调节CSC功能的参与，对 这些接收器调节CSC函数的机制尚未解决。鉴于该定位 IGF-1R或IR直接会引起重大代谢破坏，需要发展新颖 抑制这些受体活性而不破坏其正常代谢调节的方法。这 申请人的建议选择性破坏IRS2的功能，这些功能促进癌症的进展而无需 干扰其在正常代谢稳态中的作用将是一种方法。从 该提案中概述的实验将为开发有针对性的方法奠定基础 与当前的靶向CSC结合使用以治疗抗性和转移性乳腺肿瘤。到 研究以下假设：IRS2依赖性信号响应于IR/IGF-1R激活增强了CSC 自我更新并促进转移申请人将：1）确定IRS2，但不是IRS1有助于 乳房CSC的功能。 IRS2在体内增强乳腺CSC功能的假设，该调节 将检查对乳腺癌转移至关重要。 2）阐明IRS2调节的机制 CSC功能。 IRS2通过募集因子来增强CSC自我更新的假设 IRS2 C末端（SR）内与PI3K/AKT信号合作以调节CSC自我更新的区域 并将检查促进乳腺癌转移； 3）研究IR/IGF-1R信号的贡献 依赖于IRS2的CSC调节。 IR-A同工型优先启动IRS2的假设 高胰岛素血症促进肿瘤进展的信号传导以促进茎和该功能增强 将被检查。