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

项目摘要/摘要 癌症是最令人绝望的疾病之一，因为它的治疗效果有限。然而，自然 已经为治疗癌症提供了线索，特别是。与性激素相关的癌症，如肝癌和乳腺癌 癌症。雌激素，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)，这表明我们可以使用来自一种癌症的信息 来治愈另一种癌症。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，我提出了一个比较的 肝癌和乳腺癌FOXA/ER双靶点的基因组学研究 人类癌症组织和细胞以解决癌症进展的机制并确定新的 两种癌症的治疗靶点。首先，关键是要调查FOXA依赖的ER是否介导 雌激素信号也促进乳腺肿瘤的生长，这在体内还没有被研究过。我 将用Cre-loxP技术制造乳腺特异的FOXA1/2缺陷小鼠，然后研究 FOXA/ER在癌变过程中的双重调控。功能基因组学分析包括芯片序列 将进行FOXA1/2和ER以及通过微阵列和mRNA-Seq进行基因表达谱分析以确定 FOXA/ER在促进乳腺癌中的双重靶点。我们最近的研究还生成了FOXA/ER？DUAL的列表 以同样的方法预防肝癌的目标。第二，因此，比较基因组学研究 肝癌和乳腺癌之间FOXA/ER的双重靶点将被用于寻找新的治疗方法 两种癌症的靶标。类似的研究也将适用于人类癌症组织和细胞系 作为正常对照组。最后，FOXA/ER？双重靶点的组织分化调节提示存在 FOXA/ER之外的第二层监管。因此，将采用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。这不仅将提供活体证据 为癌症基因组学指导癌症治疗研究，但也将解决遗传和 对行为/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(肝脏和乳腺)或物种(小鼠和人)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).