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：
8601294
负责人：
ALAN C RAPRAEGER
金额：
$ 38.82万
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/8601294
关键词：
Angiogenic Factor Animal Model Binding Biological Assay 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 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 public health relevance receptor receptor coupling response scaffold syndecan syndecan-4 triple-negative invasive breast carcinoma tumor tumor growth tumor xenograft tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The ?4 subunit of the ?6?4 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 ?6?4 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??6?4, and syndecan-4 appears to be required by EGFR??6?4. 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）：？6？4整联蛋白的4个亚基，哪些在静态正常细胞中形成半底细胞，在过表达HER2或EGFR的乳腺肿瘤细胞中磷酸化。这种磷酸化将整联蛋白的细胞质结构域转化为信号支架，从而驱动细胞侵袭，增殖和存活。 HER2和EGFR在HER2+/ER-乳腺癌中表达，EGFR在三重阴性（HER2-，ER-，PR-）亚型中过表达。两种癌症都是高度侵略性的，并且抵抗诊所目前可用的治疗方法。由于这些癌症类型通常也过表达？6？4整合素，我们现在检查了它们对这些受体复合物信号传导的依赖。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，并且它们的信号需要与另一个基质受体家族的Syndecans组装整合素和HER2或EGFR。实际上，Syndecan-1似乎是通过HER2 ?? 6？4信号传导所必需的，而EGFR ?? 6？4似乎需要Syndecan-4。我们的目标是用这些信号传导复合物来定义联合体组装的分子细节，发展突变体和阻断肽，破坏这两个syndecans的组织功能，并在肿瘤生长，血管生成以及癌症干细胞活性中测试突变体和肽HER2+和TN乳腺癌的动物模型。这项工作的结果将为靶向HER2+和TN乳腺癌的新疗法发展提供潜在的见解。