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

描述(申请人提供)：？6？4整合素的？4亚单位，在静止的正常细胞中形成半桥粒，在过度表达HER2或EGFR的乳腺肿瘤细胞中变得磷酸化。这种磷酸化将整合素的胞浆结构域转化为一个信号支架，驱动细胞的入侵、增殖和存活。HER2和EGFR在HER2+/ER-乳腺癌中表达，EGFR在三阴性(HER2-、ER-、PR-)亚型中高表达。这两种癌症都具有很强的侵袭性，并对目前临床上可用的治疗方法产生抵抗力。由于这些类型的癌症通常也过度表达？6？4整合素，我们现在检查了它们对这些受体复合体信号的依赖性。我们已经发现，这些信号机制对于癌细胞的生长和存活是必不可少的，它们的信号需要整合素和HER2或EGFR与另一类基质受体Syndecans组装。事实上，Syndecan-1似乎是HER2？6？4信号传递所必需的，而Syndecan-4似乎是EGFR？6？4所必需的。我们的目标是确定Syndecan与这些信号复合体组装的分子细节，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乳腺癌的动物模型中测试突变体和多肽在肿瘤生长、血管生成和肿瘤干细胞活性中的作用。这项工作的结果将为针对HER2+和TN乳腺癌的新疗法的开发提供潜在的洞察力。

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.