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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.