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Role of MED1 in HER2-mediated tumorigenesis

MED1 在 HER2 介导的肿瘤发生中的作用

基本信息

批准号：
10600067
负责人：
Xiaoting Zhang
金额：
$ 37.71万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10600067
关键词：
17q12 Area Biological Assay Breast Cancer Cell Breast Cancer Patient Breast Cancer Treatment Breast cancer metastasis COPS5 gene CRISPR/Cas technology Cancer Cell Growth Cause of Death Chromosomes Clinical Cullin Proteins Data Disease Progression ERBB2 gene Estrogen Antagonists Estrogen Receptor alpha Estrogen Receptors Funding Future Gene Expression Gene Expression Profile Gene Expression Profiling Genes Genetic Transcription Goals Growth Human In Vitro Knock-in Knowledge Malignant Neoplasms Mass Spectrum Analysis Mediating Mediator Mission Modeling Molecular Mutagenesis Names Nanotechnology Neoplasm Metastasis Outcome PPARBP gene Pathway interactions Patients Play Prevention Research Process Proteins Public Health RNA Reagent Regimen Regulation Reporter Research Resistance Role Site Stains Testing Therapeutic Agents Tissue Microarray Toxic effect Transcription Coactivator Ubiquitination United States National Institutes of Health Validation Western Blotting Woman Xenograft procedure breast tumorigenesis cancer stem cell cancer therapy efficacy testing gene function human disease in vivo knock-down knowledge base malignant breast neoplasm mouse model mutant nanoparticle novel strategies novel therapeutics overexpression small hairpin RNA stem cells targeted treatment therapeutic evaluation therapy resistant thyroid hormone receptor associated protein 220 transcriptome sequencing tumorigenesis

项目摘要

Recent studies have established MED1 (Mediator Subunit 1, also named TRAP220, DRIP205, or MED220) as a key transcriptional coactivator for ERα in breast cancer. Significantly, the MED1 gene is located at the chromosome 17q12 region, also known as the HER2 amplicon, and co-amplifies with HER2 in nearly all instances in breast cancer. We have further confirmed MED1 overexpression and correlation with HER2 status at the protein level using human breast cancer tissue microarrays. Importantly, we found that MED1 serves as a crosstalk point for the HER2 and ERα pathways in ERα-mediated transcription. During our last funding period, we have established MED1 as a key mediator of HER2-driven tumorigenesis using our newly generated MED1 mutant knockin and MED1 overexpression mouse models. Here, we have provided further preliminary data supporting Jab1 as a key MED1 direct downstream target gene by unbiased RNA-seq analyses and further experimental validations. Interestingly, we found that Jab1 can also in turn regulate MED1 stability and is required for ER-dependent gene transcription and functions. The overall objective of this application is to elucidate the role and underlying molecular mechanism of Jab1/MED1 axis in HER2-mediated breast cancer. Our hypothesis is that the crosstalk between Jab1 and MED1 plays key roles in HER2-mediated breast cancer metastasis and treatment resistance. We have provided strong preliminary data, generated essential reagents, and assembled an outstanding team of collaborators to pursue the following specific aims: 1) elucidate the role and molecular mechanisms underlying Jab1 functions and regulations in breast cancer metastasis, 2) determine the role of MED1 turnover and its regulation by Jab1 in breast cancer metastasis, and 3) test the efficacy of targeting Jab1 and MED1 on breast cancer metastasis and treatment resistance. Through these studies, we expect to make an important positive impact not only by filling key knowledge gaps on the role of previously uncharacterized Jab1/MED1 regulatory loop in HER2+/ER+ breast cancer, but also by providing potential novel strategies for the future treatment of this difficult to treat subtype of breast cancer.

最近的研究已经建立了MED 1（介体亚基1，也称为TRAP 220、DRIP 205或DRIP 205）。 MED 220）作为乳腺癌中ERα的关键转录辅激活因子。值得注意的是，MED 1基因是位于染色体17 q12区域，也称为HER 2扩增子，并与HER 2共扩增，几乎所有的乳腺癌病例。我们进一步证实了MED 1的过度表达和与使用人乳腺癌组织微阵列在蛋白质水平上的HER 2状态。重要的是，我们发现，在ERα介导的转录中，MED 1是HER 2和ERα通路的串扰点。在我们在上一个资助期，我们已经建立了MED 1作为HER 2驱动的肿瘤发生的关键介质，使用我们的新产生的MED 1突变敲入和MED 1过表达小鼠模型。在这里，我们提供了进一步的初步数据支持Jab 1作为关键的MED 1直接下游靶基因，通过无偏RNA测序分析和进一步的实验验证。有趣的是，我们发现Jab 1也可以反过来调节MED 1，稳定性，并且是ER依赖性基因转录和功能所必需的。本报告的总体目标本研究旨在阐明Jab 1/MED 1轴在HER 2介导的细胞凋亡中的作用及其分子机制。乳腺癌我们的假设是Jab 1和MED 1之间的串扰在HER 2介导的细胞凋亡中起关键作用。乳腺癌转移和治疗抗性。我们提供了强有力的初步数据，基本试剂，并组建了一个杰出的合作团队，以实现以下具体目标： 1)阐明Jab 1在乳腺癌中的作用和分子机制 2）确定MED 1周转的作用和Jab 1对其在乳腺癌转移中的调节，和 3)测试靶向Jab 1和MED 1对乳腺癌转移和治疗抗性的功效。通过这些研究，我们希望不仅通过填补关键的知识空白，关于先前未表征的Jab 1/MED 1调节环在HER 2 +/ER+乳腺癌中的作用，为将来治疗这种难以治疗的乳腺癌亚型提供了潜在的新策略。