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Signaling role of syndecans in HER2+ and triple negative breast cancer

Syndecans 在 HER2 和三阴性乳腺癌中的信号作用

基本信息

批准号：
8987547
负责人：
ALAN C RAPRAEGER
金额：
$ 40.02万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8987547
关键词：
Angiogenic Factor Animal Model Binding Biological Assay Breast Cancer Cell Breast Cancer Patient Breast Carcinoma Breast Epithelial Cells Cancer Patient Cell Proliferation Cell Survival Cell surface Cells Cessation of life Clinic Complex Coupled Cytoplasmic Tail Data Death Rate Dependence Development Diagnosis Disease Dominant-Negative Mutation ECM receptor ERBB2 gene Endothelial Cells Epidermal Growth Factor Receptor Estrogen receptor negative Extracellular Domain Family Goals Growth Growth Factor Receptors Health Hemidesmosomes Homodimerization Human Integrins Lead Left Link Malignant Epithelial Cell Malignant Neoplasms Mammary Neoplasms Mediating Molecular Mus Mutate Mutation Normal Cell Outcome Patients Peptide Receptor Peptides Pharmaceutical Preparations Phosphorylation Phosphotransferases Population Process Receptor Protein-Tyrosine Kinases Receptor Signaling Refractory Resistance Role Signal Transduction Tamoxifen Testing Therapeutic Trastuzumab United States Woman Work angiogenesis breast tumorigenesis cancer cell cancer stem cell cancer type efficacy testing extracellular hormone therapy improved in vitro Model in vivo ineffective therapies inhibitor/antagonist insight killings macromolecular assembly malignant breast neoplasm mortality mouse model mutant neoplastic cell novel novel therapeutics overexpression prevent receptor receptor coupling scaffold syndecan syndecan-4 treatment response triple-negative invasive breast carcinoma tumor tumor growth tumor xenograft tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The ß4 subunit of the α6ß4 integrin, which forms hemidesmosomes in quiescent normal cells, becomes phosphorylated in breast tumor cells that overexpress HER2 or EGFR. This phosphorylation converts the cytoplasmic domain of the integrin into a signaling scaffold that drives cell invasion, proliferation and survival. HER2 and EGFR are expressed in HER2+/ER- breast cancer, and EGFR is overexpressed in the triple- negative (HER2-,ER-,PR-) subtype. Both cancers are highly aggressive and resist treatments currently available in the clinic. Because these cancer types often overexpress the α6ß4 integrin as well, we have now examined their dependence on signaling from these receptor complexes. We have discovered that these signaling mechanisms are essential for the growth and survival on the cancer cells, and that their signaling requires the assembly of the integrin and HER2 or EGFR with syndecans, another family of matrix receptors. Indeed, syndecan-1 appears necessary for signaling by HER2/α6ß4, and syndecan-4 appears to be required by EGFR/α6ß4. Our goal is to define the molecular details of syndecan assembly with these signaling complexes, develop mutants and blocking peptides that disrupt the organizing function of these two syndecans, and test the mutants and peptides in tumor growth, angiogenesis and the activity of cancer stem cells in animal models of HER2+ and TN breast cancer. The outcome of this work will provide potential insight into the development of new therapeutics to target HER2+ and TN breast cancer.

描述（由申请人提供）：α6ß4 整联蛋白的 ß4 亚基在静止的正常细胞中形成半桥粒，在过度表达 HER2 或 EGFR 的乳腺肿瘤细胞中被磷酸化。这种磷酸化将整合素的细胞质结构域转化为驱动细胞侵袭、增殖和存活的信号支架。 HER2 和 EGFR 在 HER2+/ER- 乳腺癌中表达，EGFR 在三阴性（HER2-、ER-、PR-）亚型中过度表达。这两种癌症都具有高度侵袭性，并且对临床上现有的治疗方法具有抵抗力。由于这些癌症类型通常也过度表达 α6ß4 整合素，因此我们现在检查了它们对这些受体复合物信号传导的依赖性。我们发现这些信号传导机制对于癌细胞的生长和生存至关重要，并且它们的信号传导需要整合素和 HER2 或 EGFR 与多配体（另一个基质受体家族）的组装。事实上，syndecan-1 似乎是 HER2/α6ß4 信号传导所必需的，而 syndecan-4 似乎是 EGFR/α6ß4 所必需的。我们的目标是用这些信号复合物定义多配体装配的分子细节，开发破坏这两种多配体组织功能的突变体和阻断肽，并在 HER2+ 和 TN 乳腺癌动物模型中测试突变体和肽在肿瘤生长、血管生成和癌症干细胞活性中的作用。这项工作的成果将为针对 HER2+ 和 TN 乳腺癌的新疗法的开发提供潜在的见解。