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Amphiregulin Signaling in Human Breast Cancer

人类乳腺癌中的双调蛋白信号传导

基本信息

批准号：
8247852
负责人：
STEPHEN P. ETHIER
金额：
$ 29.27万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
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/8247852
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 NF-kappa B 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 Work autocrine base cancer type chemotherapy design improved knock-down malignant breast neoplasm mutant novel novel strategies outcome forecast prognostic receptor response trafficking triple-negative invasive breast carcinoma tumorigenic young woman

项目摘要

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-kB. 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.

我们发现大约一半的基底型乳腺癌有证据表明