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

描述（由申请人提供）：癌症是最令人绝望的疾病之一，因为它的治疗成功有限。然而，《自然》已经提供了治疗癌症的线索，特别是与性激素有关的癌症，如肝癌和乳腺癌。雌激素，女性的主要性激素，对肝癌（预防）和乳腺癌（促进）的进展显示相反的作用，这表明我们可以利用一种癌症的信息来治疗另一种癌症。体外研究表明，雌激素信号通过雌激素受体α （ER¿）促进乳腺癌细胞生长依赖于叉头盒蛋白A （Foxa）。我们最近发现雌激素在体内预防肝癌也依赖于Foxa因子。因此，我建议使用体内模型和人类癌症组织和细胞对肝癌和乳腺癌之间的Foxa/ER¿双靶点进行比较基因组学研究，以解决癌症进展机制并确定两种癌症的新治疗靶点。首先，研究foxa依赖性ER¿介导的雌激素信号是否也促进乳腺肿瘤的生长是至关重要的，这一点从未在体内研究过。我将利用Cre-loxP技术制备乳腺特异性foxa1 /2缺失小鼠，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Foxa1/2和ER¿的ChIP-Seq和基因表达谱通过微阵列和mRNA-Seq来确定Foxa/ER¿促进乳腺癌的双重靶点。我们最近的研究也生成了Foxa/ER¿双重靶点列表，用同样的方法预防肝癌。其次，我们将对肝癌和乳腺癌的Foxa/ER¿双靶点进行比较基因组学研究，以确定两种癌症的新治疗靶点。类似的研究也将应用于人类癌症组织和细胞系以及正常对照。最后，Foxa/ER¿双靶点的组织差异调控表明Foxa/ER¿之外存在第二层调控。因此，蛋白质组学和表观基因组学方法将用于上述模型，以发现Foxa/ER¿的组织特异性调节因子。这不仅将为癌症基因组学指导癌症治疗研究提供体内证据，而且还将解决在不同组织（肝脏与乳腺）或物种（小鼠与人类）中表现/功能不同的同一转录因子的基因转录的遗传和表观遗传调控机制。

DESCRIPTION (provided by applicant): 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). PUBLIC HEALTH RELEVANCE: The proposed study aims to use the genomic information from one cancer to cure the other cancer. Investigating Foxa-dependent estrogen regulations in liver cancer and breast cancer will lead to discover novel therapeutic targets for both cancers.