Role of MED1 in HER2-mediated tumorigenesis

最近的研究已经建立了MED1(中介亚基1，也称为TRAP220、DRIP205或 MED220)作为乳腺癌中ERα的关键转录共激活因子。值得注意的是，MED1基因是 位于染色体17q12区域，也称为HER2扩增子，与HER2共同扩增 几乎所有的乳腺癌病例。我们进一步证实了MED1的过度表达和与 人乳腺癌组织芯片在蛋白质水平上的HER2状态。重要的是，我们发现 在ERα介导的转录过程中，MED 1是HER2和ERα途径的串音点。在我们的 在上个资助期，我们利用我们的 新产生的MED_1突变型敲门蛋白和MED_1过表达小鼠模型。在这里，我们提供了 进一步的初步数据支持Jab1作为一个关键的MED1直接下游靶基因 分析和进一步的实验验证。有趣的是，我们发现Jab1也可以反过来调节MED1 稳定性，是内质网依赖基因转录和功能所必需的。这样做的总体目标是 应用于阐明Jab1/MED1轴在HER2介导中的作用和潜在的分子机制 乳腺癌。我们的假设是，Jab1和MED1之间的串扰在HER2介导的信号传导中起关键作用 乳腺癌的转移与治疗耐药。我们提供了强大的初步数据，生成 基本试剂，并组建了一支优秀的合作者团队，以实现以下具体目标： 1)阐明Jab1在乳腺癌中的作用和分子机制 转移，2)确定MED1的更新在乳腺癌转移中的作用及Jab1对其的调节，以及 3)检测靶向Jab1和MED1对乳腺癌转移和耐药的影响。 通过这些研究，我们期望产生重要的积极影响，不仅是通过填补关键的知识空白 关于先前未知的Jab1/MED1调控环在HER2+/ER+乳腺癌中的作用，但也通过 为这一难治亚型乳腺癌的未来治疗提供了潜在的新策略。

Recent studies have established MED1 (Mediator Subunit 1, also named TRAP220, DRIP205, or MED220) as a key transcriptional coactivator for ERα in 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 nearly all instances in breast cancer. We have further 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 crosstalk point for the HER2 and ERα pathways in ERα-mediated transcription. During our last funding period, we have established MED1 as a key mediator of HER2-driven tumorigenesis using our newly generated MED1 mutant knockin and MED1 overexpression mouse models. Here, we have provided further preliminary data supporting Jab1 as a key MED1 direct downstream target gene by unbiased RNA-seq analyses and further experimental validations. Interestingly, we found that Jab1 can also in turn regulate MED1 stability and is required for ER-dependent gene transcription and functions. The overall objective of this application is to elucidate the role and underlying molecular mechanism of Jab1/MED1 axis in HER2-mediated breast cancer. Our hypothesis is that the crosstalk between Jab1 and MED1 plays key roles in HER2-mediated breast cancer metastasis and treatment resistance. We have provided strong preliminary data, generated essential reagents, and assembled an outstanding team of collaborators to pursue the following specific aims: 1) elucidate the role and molecular mechanisms underlying Jab1 functions and regulations in breast cancer metastasis, 2) determine the role of MED1 turnover and its regulation by Jab1 in breast cancer metastasis, and 3) test the efficacy of targeting Jab1 and MED1 on breast cancer metastasis and treatment resistance. Through these studies, we expect to make an important positive impact not only by filling key knowledge gaps on the role of previously uncharacterized Jab1/MED1 regulatory loop in HER2+/ER+ breast cancer, but also by providing potential novel strategies for the future treatment of this difficult to treat subtype of breast cancer.