Role of MED1 in HER2-driven Breast Tumorigenesis

 描述(由申请人提供)：最近的研究证实，MED1(中介亚单位1，也称为TRAP220、DRIP205或MED220)是ER在正常乳腺发育和乳腺癌过程中的关键转录共激活因子。值得注意的是，MED1基因位于染色体17q12区域，也被称为HER2扩增子，并在几乎所有乳腺癌病例中与HER2共同扩增。我们最近利用人类乳腺癌组织微阵列在蛋白质水平上证实了MED1的过度表达及其与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治疗的耐药性的关键串音点。然而，尽管最近取得了进展，但MED1及其过度表达是否在HER2驱动的肿瘤发生中发挥作用仍是未知的。为此，我们将MMTV-HER2乳腺肿瘤小鼠与我们建立的MED1突变敲击小鼠和新产生的MED1乳腺特异过表达小鼠进行了杂交。我们发现，在MED1突变敲击小鼠中，MMTV-HER2肿瘤的进展显著减缓，极大地抑制了肿瘤向肺的转移，并降低了肿瘤乳房的形成能力。相反，我们观察到与MMTV-HER2小鼠相比，MMTV-HER2/MMTV-MED1双转基因小鼠的肿瘤发生、生长、多样性和肿瘤转移显著加快。基于这些发现，我们的中心假设是MED1在HER2介导的肿瘤发生中是必需的，靶向MED1通路可能是治疗HER2+ER+乳腺癌亚型的有用策略，由于抗雌激素和抗HER2治疗的耐药性，临床上该亚型的治疗具有挑战性。 我们将结合生物化学、纳米技术和小鼠遗传学方法，1)阐明MED1在HER2介导的肿瘤发生中的潜在分子机制；2)确定MED1过表达在HER2介导的肿瘤发生中的作用；以及3)在体内外测试针对MED1途径在HER2高表达的人乳腺癌细胞中的有效性。通过这些研究，我们希望确定MED1及其下游的关键分子通路在HER2驱动的乳腺肿瘤发生中的作用。本申请中提出的研究具有创新性，因为我们正在利用我们独特的MED1突变和新产生的MED1过表达小鼠模型来阐明MED1在乳腺癌干细胞形成和转移中的作用和潜在的分子机制。这项研究也具有重要意义，因为它有望填补关于共扩增基因(MED1)的作用及其与HER2扩增子上的驱动因素(HER2)在肿瘤发生中的相互作用的关键知识空白，并通过为潜在的人类乳腺癌治疗提供基于RNA纳米技术的新疗法而产生积极影响。

 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.