Role of MED1 in HER2-driven Breast Tumorigenesis

 描述（由申请人提供）：最近的研究已经确定MED 1（介体亚基1，也称为TRAP 220、DRIP 205或MED 220）是正常乳腺发育和乳腺癌期间ER β的关键转录辅激活因子。值得注意的是，MED 1基因位于染色体17 q12区域，也称为HER 2扩增子，并且在几乎所有乳腺癌病例中与HER 2共扩增。我们最近证实了MED 1过表达和HER 2状态的相关性，在蛋白质水平上使用人类乳腺癌组织微阵列。重要的是，我们发现MED 1是HER 2和ER β通路ER β介导的转录和乳腺癌细胞对抗雌激素治疗的抗性的关键串扰点。然而，尽管最近取得了进展，MED 1及其过表达是否在HER 2驱动的肿瘤发生中发挥作用仍然是未知的。为此，我们将MMTV-HER 2乳腺肿瘤小鼠与我们建立的MED 1突变敲入小鼠和新产生的MED 1乳腺特异性过表达小鼠杂交。我们发现，在MED 1突变敲入小鼠中，MMTV-HER 2肿瘤的进展显著降低，肿瘤向肺的转移受到极大抑制，肿瘤乳腺球形成能力降低。相反，我们观察到与MMTV-HER 2小鼠相比，MMTV-HER 2/MMTV-MED 1双转基因小鼠的肿瘤发病、生长、多样性和肿瘤转移显著加速。基于这些发现，我们的中心假设是MED 1是HER 2介导的肿瘤发生所必需的，靶向MED 1通路可能是治疗HER 2 +ER+乳腺癌亚型的有用策略，该亚型由于对抗雌激素和抗HER 2疗法的耐药性而具有临床治疗挑战性。 我们将利用生物化学、纳米技术和小鼠遗传学方法的组合来1）阐明MED 1在HER 2介导的肿瘤发生中功能的分子机制; 2）确定MED 1过表达在HER 2介导的肿瘤发生中的作用;和3）测试靶向HER 2的功效HER 2过表达的人乳腺癌细胞中的MED 1途径体外和体内。通过这些研究，我们希望确定MED 1及其关键下游分子通路在HER 2驱动的乳腺肿瘤发生中的作用。本申请中提出的研究是创新的，因为我们正在利用我们独特的MED 1突变体和新生成的MED 1过表达小鼠模型来阐明MED 1在乳腺癌干细胞形成和转移中的作用和潜在的分子机制。这项研究也很重要，因为它有望填补关于共扩增基因（MED 1）的作用及其与HER 2扩增子中驱动基因（HER 2）的相互作用的关键知识空白，并通过提供新的基于RNA纳米技术的治疗方法来产生积极影响。

 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.