Comparative Genomics Study of Foxa/ER Targets in Liver Cancer and Breast Cancer

项目概要/摘要 由于治疗效果有限，癌症是最令人绝望的疾病之一。然而，大自然 已经提供了治疗癌症的线索，特别是。用于与性激素相关的癌症，如肝癌和乳腺癌 癌症。雌激素是女性主导的性激素，对肝脏的进展表现出相反的作用 癌症（预防）和乳腺癌（促进），表明我们可以使用一种癌症的信息 治愈其他癌症。体外研究表明，雌激素信号通过雌激素受体α (ER¿) 促进乳腺癌细胞的生长依赖于叉头盒蛋白A（Foxa）。我们最近发现 雌激素预防肝癌还依赖于体内的Foxa因子。因此，我提出一个比较 使用体内模型对肝癌和乳腺癌之间的双靶点 Foxa/ER 进行基因组学研究 人类癌症组织和细胞，以解决癌症进展的机制并识别新的 两种癌症的治疗靶点。首先，研究 Foxa 依赖性 ER 是否介导至关重要 雌激素信号还促进乳腺肿瘤生长，这一点尚未在体内研究过。我 将利用 Cre-loxP 技术制造乳腺特异性 Foxa1/2 缺陷小鼠，然后进行研究 Foxa/ER¿ 致癌过程中的双重调节。功能基因组学分析，包括 ChIP-Seq Foxa1/2 和 ER¿ 以及通过微阵列和 mRNA-Seq 进行的基因表达谱分析将被用来鉴定 Foxa/ER¿ 促进乳腺癌的双重目标。我们最近的研究还生成了 Foxa/ER 双重列表 用同样的方法来预防肝癌。其次，因此，比较基因组学研究 Foxa/ER¿ 肝癌和乳腺癌之间的双重靶点将被寻求以确定新的治疗方法 两种癌症的靶标。类似的研究也将应用于人类癌症组织和细胞系 作为正常对照。最后，Foxa/ER 双重靶标的组织差异调节表明存在 Foxa/ER 之外的第二层监管。因此，将寻求蛋白质组学和表观基因组学方法 在上述模型上发现 Foxa/ER 的组织特异性调节因子。这不仅可以提供活体证据 癌症基因组学指导癌症治疗研究，但也将解决遗传和癌症的机制 表现/功能不同的同一转录因子的基因转录的表观遗传调控 在不同的组织（肝脏与乳腺）或物种（小鼠与人类）中。

Project Summary/Abstract Cancer is one of the most desperate diseases due to the limited success of its treatment. However, Nature already provides clues for curing cancer, esp. for sexual hormone-related cancers, like liver cancer and breast cancer. Estrogen, the female dominating sexual hormone, shows opposite effects on the progression of liver cancer (preventing) and breast cancer (promoting), indicating that we may use the information from one cancer to cure the other cancer. In vitro studies show that estrogen signaling through estrogen receptor alpha (ER¿) in promoting the growth of breast cancer cells relies on forkhead box protein A (Foxa). We found recently that estrogen preventing liver cancer also depends on Foxa factors in vivo. Thus, I propose a comparative genomics study of Foxa/ER¿ dual targets between liver cancer and breast cancer using in vivo models and human cancer tissues and cells to address the mechanisms of cancer progression and to identify novel therapeutic targets for both cancers. First, it is critical to investigate whether Foxa-dependent ER¿-mediated estrogen signaling also promote the tumor growth in mammary gland, which has never been studied in vivo. I will make mammary gland-specific Foxa1/2-deficeint mice with the Cre-loxP technology and then investigate Foxa/ER¿ dual regulations during carcinogenesis. Functional genomics analysis including ChIP-Seq of Foxa1/2 and ER¿ and gene expression profiling by microarrays and mRNA-Seq will be pursued to identify Foxa/ER¿ dual targets in facilitating breast cancer. Our recent study also generated a list of Foxa/ER¿ dual targets in preventing liver cancer with the same approach. Secondly, therefore, a comparative genomics study of Foxa/ER¿ dual targets between liver cancer and breast cancer will be pursued to identify novel therapeutic targets for both cancers. The similar studies will also be applied to human cancer tissues and cell lines as well as normal controls. Lastly, tissue-differential regulations of Foxa/ER¿ dual targets indicate the existence of the second layer of regulation beyond Foxa/ER¿. Thus, proteomics and epigenomics approaches will be pursued on above models to discover tissue-specific regulators of Foxa/ER¿. This will not only provide in vivo evidence for cancer genomics to guide cancer therapeutic studies, but will also address the mechanisms of genetic and epigenetic regulation of gene transcription of the same transcription factor that behaves/functions differentially in different tissues (liver versus mammary gland) or species (mouse versus human).