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:
- 金额:$ 38.82万
- 依托单位:
- 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:
- 关键词:Angiogenic FactorAnimal ModelBindingBiological AssayBreast CarcinomaBreast Epithelial CellsCancer PatientCell ProliferationCell SurvivalCell surfaceCellsCessation of lifeClinicComplexCoupledCytoplasmic TailDataDeath RateDependenceDevelopmentDiagnosisDiseaseDominant-Negative MutationECM receptorERBB2 geneEndothelial CellsEpidermal Growth Factor ReceptorEstrogen receptor negativeExtracellular DomainFamilyGoalsGrowthGrowth Factor ReceptorsHemidesmosomesHomodimerizationHumanIntegrinsLeadLeftLinkMalignant Epithelial CellMalignant NeoplasmsMammary NeoplasmsMediatingMolecularMusMutateMutationNormal CellOutcomePatientsPeptide ReceptorPeptidesPharmaceutical PreparationsPhosphorylationPhosphotransferasesPopulationProcessReceptor Protein-Tyrosine KinasesReceptor SignalingRefractoryResistanceRoche brand of trastuzumabRoleSignal TransductionTamoxifenTestingTherapeuticUnited StatesWomanWorkangiogenesisbreast tumorigenesiscancer cellcancer stem cellcancer typeefficacy testingextracellularhormone therapyimprovedin vitro Modelin vivoinhibitor/antagonistinsightkillingsmacromolecular assemblymalignant breast neoplasmmortalitymouse modelmutantneoplastic cellnovelnovel therapeuticsoverexpressionpreventpublic health relevancereceptorreceptor couplingresponsescaffoldsyndecansyndecan-4triple-negative invasive breast carcinomatumortumor growthtumor xenografttumorigenesis
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):该?4亚单位的?六个?在静止的正常细胞中形成半桥粒的4整合素在过表达HER 2或EGFR的乳腺肿瘤细胞中变得磷酸化。这种磷酸化将整合素的胞质结构域转化为驱动细胞侵袭、增殖和存活的信号传导支架。HER 2和EGFR在HER 2 +/ER-乳腺癌中表达,EGFR在三阴性(HER 2-、ER-、PR-)亚型中过表达。这两种癌症都是高度侵袭性的,并且抵抗目前临床上可用的治疗。因为这些癌症类型通常过度表达?六个?4整合素,我们现在已经检查了它们对来自这些受体复合物的信号传导的依赖性。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是必不可少的,并且它们的信号传导需要整合素和HER 2或EGFR与多配体蛋白聚糖(另一种基质受体家族)的组装。事实上,syndecan-1似乎是HER 2??六个?4,syndecan-4似乎是EGFR?六个?4.我们的目标是确定与这些信号复合物的syndecan组装的分子细节,开发突变体和阻断肽,破坏这两个syndecan的组织功能,并测试突变体和肽在肿瘤生长,血管生成和肿瘤干细胞的活性在HER 2+和TN乳腺癌的动物模型。这项工作的结果将为靶向HER 2+和TN乳腺癌的新疗法的开发提供潜在的见解。
项目成果
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ALAN C RAPRAEGER其他文献
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{{ truncateString('ALAN C RAPRAEGER', 18)}}的其他基金
A kinase-independent role for EGFR in p38MAPK suppression and S-phase progression in head and neck cancer
EGFR 在头颈癌 p38MAPK 抑制和 S 期进展中的激酶独立作用
- 批准号:
9885259 - 财政年份:2020
- 资助金额:
$ 38.82万 - 项目类别:
A kinase-independent role for EGFR in p38MAPK suppression and S-phase progression in head and neck cancer
EGFR 在头颈癌 p38MAPK 抑制和 S 期进展中的激酶独立作用
- 批准号:
10392360 - 财政年份:2020
- 资助金额:
$ 38.82万 - 项目类别:
Syndecan-1 (CD138) and its synstatins: targeting invasion, survival and angiogenesis in myeloma
Syndecan-1 (CD138) 及其 Synstatins:靶向骨髓瘤的侵袭、存活和血管生成
- 批准号:
9383657 - 财政年份:2017
- 资助金额:
$ 38.82万 - 项目类别:
Syndecan-1 (CD138) and its synstatins: targeting invasion, survival and angiogenesis in myeloma
Syndecan-1 (CD138) 及其 Synstatins:靶向骨髓瘤的侵袭、存活和血管生成
- 批准号:
10208798 - 财政年份:2017
- 资助金额:
$ 38.82万 - 项目类别:
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
- 批准号:
8777946 - 财政年份:2013
- 资助金额:
$ 38.82万 - 项目类别:
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
- 批准号:
8439629 - 财政年份:2013
- 资助金额:
$ 38.82万 - 项目类别:
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
- 批准号:
8987547 - 财政年份:2013
- 资助金额:
$ 38.82万 - 项目类别:
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