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：α6ß4的ß4亚基在静止正常中形成半透胶体，在乳腺肿瘤细胞中被损坏，过表达HER2或硫化会转化整联蛋白内无氧D的细胞胞质结构域，该结构蛋白drogent d驱动细胞入侵，HER2和EGFR在HER2+/ER-/ER--/ER- ER-ER-- ER-ER--乳腺癌，er-，Pr-）亚型。癌细胞的信号是HER2/α6ß4信号所需的Syndecan-1和Ecan-1 Rs，而Syndecan-4似乎是EGFR/α6ß4所需的。并阻止syndecans的腐蚀功能，并在HER2+和TN乳腺癌的肿瘤生长模型中测试较小的毒性和肽。