Amphiregulin Signaling in Human Breast Cancer

人类乳腺癌中的双调蛋白信号传导

• 批准号: 8058692
• 负责人: STEPHEN P. ETHIER
• 金额: $ 16.95万
• 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 2012-01-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8058692
• 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础型乳腺癌显示双调节蛋白（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会发生显著改变，从而建立一个涉及NF-？B和IL-1，一种独特的转录谱的表达，以及获得运动和侵袭能力。本研究的首要目标是阐明AREG如何从根本上改变人类乳腺癌细胞的生物学特性，促进侵袭性人类乳腺癌表型特征的表达，并验证AREG的作用是通过NF-激活介导的假设。B和IL-1。该项目的具体目的是：1)验证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-活化的EGFR信号改变的近似机制。B和IL-1的表达2)确定AREG刺激细胞中EGFR信号体的成分，阐明AREG激活的EGFR到核内NF-积累的信号通路。B，并分析该途径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信号如何通过影响靶向EGFR的酪氨酸磷酸酶和/或酪氨酸激酶的活性，调节乳腺癌细胞和具有AREG/EGFR自分泌环的乳腺上皮细胞中的EGFR酪氨酸磷酸化。4)确定在有AREG/EGFR自分泌环的乳腺癌中，EGFR抑制是否导致IL-1下调，NF- B核缺失。AREG激活EGFR从根本上改变了HME细胞的生物学特性，诱导了高侵袭性和耐药乳腺癌细胞表达的表型。了解这种差异的机制基础，以及了解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的生物学理解，这种癌症除了标准化疗之外没有其他治疗选择。