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.

Public Health Relevance

This proposal is relevant to public health because it aims to understand the role of a key ER co-activator (MED1) in HER2-driven breast tumorigenesis in the process of cancer growth, stem cell formation and metastasis. Completion of the study is expected to not only broaden our knowledge base in these areas, but will also provide potential new therapeutic agents for the treatment of human breast cancer. Thus, the proposed research is relevant to the mission of NIH to conduct research for the prevention and cure of human diseases.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Progression and Metastasis Study Section (TPM)
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University of Cincinnati
Anatomy/Cell Biology
Schools of Medicine
United States
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Yang, Yongguang; Leonard, Marissa; Zhang, Yijuan et al. (2018) HER2-Driven Breast Tumorigenesis Relies upon Interactions of the Estrogen Receptor with Coactivator MED1. Cancer Res 78:422-435
Zhang, Yijuan; Leonard, Marissa; Shu, Yi et al. (2017) Overcoming Tamoxifen Resistance of Human Breast Cancer by Targeted Gene Silencing Using Multifunctional pRNA Nanoparticles. ACS Nano 11:335-346