Syndecans 在 HER2 和三阴性乳腺癌中的信号作用-猫眼课题宝

Syndecans 在 HER2 和三阴性乳腺癌中的信号作用

批准号：

8777946

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

项目状态：

已结题

起止时间：

2013-01-01 至 2015-12-31

来源：

https://reporter.nih.gov/project-details/8777946

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 Roche brand of trastuzumab Role Signal Transduction Tamoxifen Testing Therapeutic 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 inhibitor/antagonist insight killings macromolecular assembly malignant breast neoplasm mortality mouse model mutant neoplastic cell novel novel therapeutics overexpression prevent receptor receptor coupling response scaffold syndecan syndecan-4 triple-negative invasive breast carcinoma tumor tumor growth tumor xenograft tumorigenesis

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中文摘要

翻译

描述（由申请人提供）：α6ß4整合素的ß4亚基在静止的正常细胞中形成半脂粒，在过表达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-）亚型中过表达。这两种癌症都具有很强的侵袭性，对目前临床可用的治疗方法都有抗药性。因为这些癌症类型也经常过度表达α6ß4整合素，我们现在已经研究了它们对这些受体复合物信号的依赖性。我们已经发现这些信号传导机制对于癌细胞的生长和存活至关重要，并且它们的信号传导需要整合素和HER2或EGFR与syndecans（另一种基质受体家族）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。我们的目标是确定syndecan与这些信号复合物组装的分子细节，开发破坏这两种syndecan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对肿瘤生长、血管生成和癌症干细胞活性的影响。这项工作的结果将为开发针对HER2+和TN乳腺癌的新疗法提供潜在的见解。

英文摘要

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.

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