Amphiregulin Signaling in Human Breast Cancer

人类乳腺癌中的双调蛋白信号传导

• 批准号: 7880221
• 负责人: STEPHEN P. ETHIER
• 金额: $ 31.54万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7880221
• 关键词: Amphiregulin; Applications Grants; Biology; Breast Cancer Cell; Cell surface; Cells; Characteristics; Data; Disease; Down-Regulation; Drug resistance; EGF gene; ERBB2 gene; Epidermal Growth Factor Receptor; Epithelial Cells; Estrogen Receptors; Feedback; Gene Expression; Generations; Genetic Transcription; Goals; Growth; Human; Interleukin-1; Ligands; Mammary Neoplasms; Mammary gland; Mediating; Molecular; Molecular Analysis; Natural History; Nuclear; Pathway interactions; Patients; Phenotype; Phosphorylation; Prevalence; Progesterone Receptors; Protein Tyrosine Kinase; Protein Tyrosine Phosphatase; Public Health; Receptor Activation; Receptor Inhibition; Receptor Signaling; Recycling; Research; Role; Signal Pathway; Signal Transduction; Specimen; Stream; Testing; Therapeutic; Tyrosine Phosphorylation; Woman; Work; autocrine; base; cancer type; chemotherapy; design; improved; knock-down; malignant breast neoplasm; mutant; novel; novel strategies; outcome forecast; prognostic; public health relevance; receptor; response; trafficking; triple-negative invasive breast carcinoma; tumorigenic

DESCRIPTION (provided by applicant): We have found that approximately half of basal type breast cancers show evidence for autocrine activation of the EGFR by amphiregulin (AREG). Furthermore, our data indicate that when AREG is the activating ligand for EGFR, receptor trafficking and down stream signaling is dramatically altered resulting in the establishment of a positive feedback loop involving NF-?B and IL-1, the expression of a distinctive transcription profile, and the acquisition of motile and invasive capacity. The over arching goal of the work proposed in this application is to elucidate how AREG fundamentally alters the biology of human breast cancer cells and contributes to the expression of phenotypes characteristic of aggressive human breast cancer, and to test the hypothesis that AREG's effects are mediated via activation of NF-?B and IL-1. The specific aims of this project are: 1) To test the hypothesis that accumulation of EGFR at the cell surface, which occurs in AREG stimulated cells and not EGF-stimulated cells, is the proximate mechanism for the altered EGFR signaling that results in activation of NF-?B and expression of IL-1, 2) To determine the components of the EGFR signalosome in AREG stimulated cells, to elucidate the signaling pathway from AREG-activated EGFR to the nuclear accumulation of NF-?B, and to analyze the role of this pathway in the expression of aggressive growth phenotypes of basal breast cancer cells, 3) To determine how IL-1 signaling modulates EGFR tyrosine phosphorylation in breast cancer cells and mammary epithelial cells with an AREG/EGFR autocrine loop by influencing the activity of tyrosine phosphatases and/or tyrosine kinases that target EGFR, and 4) to determine if EGFR-inhibition in breast cancers with AREG/EGFR autocrine loops results in down-regulation of IL-1, and loss of nuclear of NF-?B. AREG activation of EGFR fundamentally alters the biology of HME cells and induces phenotypes expressed by highly aggressive and drug-resistant breast cancer cells. Understanding the mechanistic basis for this difference, and understanding the downstream consequences of AREG mediated activation of the EGFR will improve our understanding of the biology of a particularly aggressive subclass of breast cancer for which there are no therapeutic options beyond standard chemotherapy. PUBLIC HEALTH RELEVANCE: The research that is proposed in this grant application is aimed at understanding the mechanistic basis for the aggressive growth of a particular type of human breast cancer that tends to occur in younger women and which carries a very poor prognosis. Improving our understanding of the pathways that drive this disease will impact our ability to design novel targeted therapies for patients with this type of breast cancer. Given that current forms of therapy for these cancer types are ineffective, developing novel strategies to more effectively treat patients with the most aggressive type of breast cancer will have a positive impact on public health.

描述（由申请人提供）：我们发现大约一半的基底型乳腺癌显示出双调蛋白 (AREG) 自分泌激活 EGFR 的证据。此外，我们的数据表明，当 AREG 是 EGFR 的激活配体时，受体运输和下游信号传导发生显着改变，导致建立涉及 NF-κB 和 IL-1 的正反馈环、独特转录谱的表达以及运动和侵袭能力的获得。本申请提出的工作的首要目标是阐明 AREG 如何从根本上改变人类乳腺癌细胞的生物学特性并有助于侵袭性人类乳腺癌表型特征的表达，并检验 AREG 的作用是通过 NF-κB 和 IL-1 激活介导的假设。该项目的具体目标是：1) 检验以下假设：EGFR 在细胞表面的积累（发生在 AREG 刺激的细胞而不是 EGF 刺激的细胞中）是导致 NF-κB 激活和 IL-1 表达的 EGFR 信号传导改变的直接机制，2) 确定 AREG 刺激的细胞中 EGFR 信号体的成分，以阐明来自 AREG 激活 EGFR 到 NF-κB 的核积聚，并分析该通路在基底乳腺癌细胞侵袭性生长表型表达中的作用，3) 确定 IL-1 信号如何通过影响酪氨酸磷酸酶和/或 4) 确定具有 AREG/EGFR 自分泌环的乳腺癌中的 EGFR 抑制是否会导致 IL-1 下调和 NF-κB 核丢失。 EGFR 的 AREG 激活从根本上改变了 HME 细胞的生物学特性，并诱导高度侵袭性和耐药性乳腺癌细胞表达的表型。了解这种差异的机制基础，并了解 AREG 介导的 EGFR 激活的下游后果，将提高我们对一种特别具有侵袭性的乳腺癌亚类生物学的理解，对于这种乳腺癌，除了标准化疗之外没有其他治疗选择。 公共健康相关性：本拨款申请中提出的研究旨在了解特定类型人类乳腺癌侵袭性生长的机制基础，这种乳腺癌往往发生在年轻女性中，且预后非常差。提高我们对导致这种疾病的途径的理解将影响我们为此类乳腺癌患者设计新型靶向疗法的能力。鉴于目前对这些癌症类型的治疗形式无效，开发新策略来更有效地治疗最具侵袭性的乳腺癌患者将对公众健康产生积极影响。