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：
10445621
负责人：
Xiaoting Zhang
金额：
$ 38.48万
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/10445621
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 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 of activation protein 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 base 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Med1（调解员亚基1，也称为陷阱220，DRIP205或 Med220）作为乳腺癌中ERα的关键转录共激活因子。值得注意的是，Med1基因是位于17q12染色体区域，也称为HER2 Amplicon，并与HER2共扩增几乎所有的乳腺癌实例。我们进一步确认了Med1的过表达和与使用人类乳腺癌组织微阵列在蛋白质水平上的HER2状态。重要的是，我们发现 Med1是ERα介导的转录中HER2和ERα途径的串扰点。在我们期间最后的资金期，我们将Med1建立为HER2驱动肿瘤发生的关键调解人新生成的MED1突变型敲击蛋白和Med1过表达小鼠模型。在这里，我们提供了通过公正的RNA-Seq，进一步支持JAB1作为关键MED1直接下游靶基因的初步数据分析和进一步的实验验证。有趣的是，我们发现JAB1也可以调节Med1 稳定性，是ER依赖性基因转录和功能所必需的。总体目标应用是阐明HER2介导的JAB1/MED1轴的作用和潜在的分子机制乳腺癌。我们的假设是Jab1和Med1之间的串扰在HER2介导的乳腺癌转移和治疗耐药性。我们提供了强大的初步数据，生成了基本试剂，并组建了一支杰出的合作者团队，以追求以下特定目标： 1）阐明乳腺癌中JAB1功能和法规的作用和分子机制转移，2）确定Med1周转及其对JAB1在乳腺癌转移中的调节的作用，以及 3）测试靶向JAB1和MED1对乳腺癌转移和治疗耐药性的效率。通过这些研究，我们希望不仅通过填补关键知识差距产生重要的积极影响关于先前未表征的JAB1/MED1调节环在HER2+/ER+乳腺癌中的作用，也是通过提供潜在的新型策略，以对这种难以治疗乳腺癌亚型的未来治疗。