Role of MED1 in HER2-driven Breast Tumorigenesis

MED1 在 HER2 驱动的乳腺肿瘤发生中的作用

基本信息

批准号：
8944439
负责人：
Xiaoting Zhang
金额：
$ 36.14万
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 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8944439
关键词：
17q12 Affect Area Biochemical Biological Assay Breast Cancer Cell Breast Cancer Model Cancer Cell Growth Cause of Death Cells ChIP-on-chip Chromosomes Data Development Disease Disease Progression Doxycycline ERBB2 gene Estrogen Antagonists Estrogen Receptors Estrogen Therapy Future Gene Expression Genes Genetic Transcription Goals Growth Human In Vitro Insulin-Like Growth Factor I Knowledge MCF7 cell Malignant Neoplasms Mammary Neoplasms Mammary gland Mediating Mediator of activation protein Metastatic Neoplasm to the Lung Mission Molecular Molecular Biology Molecular Profiling Mouse Mammary Tumor Virus Mus Names Nanotechnology Neoplasm Metastasis Outcome PPARBP gene Pathway interactions Patients Phosphorylation Play Prevention Research Process Progesterone Receptors Proteins Protocols documentation Public Health RNA Reagent Regulation Research Resistance Role Small Interfering RNA Staining method Stains Stem cells System Testing Therapeutic Therapeutic Agents Tissue Microarray Transcription Coactivator Transgenic Mice Transgenic Organisms Transplantation United States National Institutes of Health Woman Xenograft procedure base breast tumorigenesis cancer stem cell efficacy testing genetic approach human disease in vivo innovation insight knowledge base malignant breast neoplasm mammary gland development mouse model mutant nano nanoparticle neoplastic cell novel novel strategies novel therapeutics overexpression public health relevance skills small hairpin RNA stem therapeutic target thyroid hormone receptor associated protein 220 treatment strategy tumor tumor growth tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Recent studies have established MED1 (Mediator Subunit 1, also named TRAP220, DRIP205, or MED220) as a key transcriptional coactivator for ER during both normal mammary gland development and 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 almost all instances in breast cancer. We have recently 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 key crosstalk point for the HER2 and ER pathways ER-mediated transcription and resistance of breast cancer cells to anti-estrogen therapies. However, despite recent progress, whether MED1 and its overexpression play a role in HER2-driven tumorigenesis is still unknown. Towards that end, we have crossed MMTV-HER2 mammary tumor mice with our established MED1 mutant knockin mice and newly generated MED1 mammary-specific overexpression mice. We found that the progression of MMTV-HER2 tumors is dramatically reduced in MED1 mutant knockin mice, with greatly inhibited tumor metastasis to lung and decreased tumor mammosphere formation capability. Conversely, we observed significantly accelerated tumor onset, growth, multiplicity, and tumor metastasis in MMTV-HER2/MMTV-MED1 double transgenic mice compared to MMTV-HER2 mice. Based on these findings, our central hypothesis is that MED1 is required for HER2-mediated tumorigenesis, and targeting the MED1 pathway could be a useful strategy for treatment of the HER2+ER+ breast cancer subtype that is clinically challenging to treat due to resistance to both anti-estrogen and anti-HER2 therapies. We will utilize a combination of biochemical, nano-technological, and mouse genetic approaches to 1) elucidate the molecular mechanisms underlying MED1 functions in HER2-mediated tumorigenesis; 2) determine the role of MED1 overexpression in HER2-mediated tumorigenesis; and 3) test the efficacy of targeting the MED1 pathway in HER2-overexpressing human breast cancer cells in vitro and in vivo. Through these studies, we expect to identify the role of MED1 and its key downstream molecular pathways involved in HER2-driven breast tumorigenesis. The research proposed in this application is innovative because we are utilizing our unique MED1 mutant and newly generated MED1 overexpression mouse models to elucidate the role and underlying molecular mechanism of MED1 regarding its previously undescribed functions in breast cancer stem cell formation and metastasis. This study is also significant because it is expected to fill a key knowledge gap on the role of a co-amplified gene (MED1) and its interplay with the driver (HER2) at the HER2 amplicon in tumorigenesis, and to make a positive impact by providing novel RNA nanotechnology-based therapeutics for potential treatment of human breast cancer.

描述（由适用提供）：最近的研究已经建立了Med1（中介亚基1，也称为TRAP220，DRIP205或MED220）为正常乳腺发育和乳腺癌期间ER的关键转录共激活因子。值得注意的是，MED1基因位于17q12染色体区域，也称为HER2扩增子，在乳腺癌的几乎所有情况下都与HER2共扩增。我们最近使用人类乳腺癌组织微阵列证实了MED1的过表达和与HER2状态的相关性。重要的是，我们发现MED1是HER2和ER途径ER介导的转录和乳腺癌细胞对抗雌激素疗法的转录和耐药性的关键串扰点。然而，dospite最近的进步，MED1及其过表达在HER2驱动的肿瘤发生中是否发挥作用。为此，我们已经将MMTV-HER2乳腺肿瘤小鼠与已建立的Med1突变型敲击蛋白小鼠和新产生的Med1乳腺特异性过表达小鼠越过MMTV-HER2乳腺肿瘤小鼠。我们发现，MMTV-HER2肿瘤的进展大大降低了MED1突变型小鼠，肿瘤转移到肺部大大抑制，并改善了肿瘤乳腺瘤的形成能力。相反，与MMTV-HER2小鼠相比，我们观察到MMTV-HER2/MMTV-MED1双转基因小鼠的肿瘤发作，生长，多重性和肿瘤转移。基于这些发现，我们的中心假设是MED1是HER2介导的肿瘤发生所必需的，而靶向MED1途径可能是治疗HER2+ ER+乳腺癌亚型的有用策略，由于对抗雌激素和抗HEH2疗法的耐药性在临床上具有挑战性。我们将利用生化，纳米技术和小鼠遗传学方法的结合1）阐明HER2介导的肿瘤发生中Med1功能的分子机制； 2）确定Med1过表达在HER2介导的肿瘤发生中的作用； 3）测试在体外和体内靶向HER2过表达的人类乳腺癌细胞中Med1途径的效率。通过这些研究，我们期望确定Med1及其关键下游分子途径与HER2驱动的乳腺肿瘤发生的作用。该应用中提出的研究具有创新性，因为我们利用我们独特的MED1突变体和新生成的Med1过表达小鼠模型来阐明Med1在其先前未描述的乳腺癌干细胞形成和转移中的作用和基本的分子机制。这项研究也很重要，因为预计它将填补有关共同膨胀基因（MED1）的作用的关键知识差距及其与HER2 Amplicon在肿瘤发生中的驾驶员（HER2）的相互作用（HER2）的相互作用，并通过提供基于RNA纳米技术的新型纳米技术治疗来对人类乳腺癌的潜在治疗产生积极影响。