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

肝癌和乳腺癌中 Foxa/ER 靶点的比较基因组学研究

• 批准号: 8608502
• 负责人: Zhaoyu Li
• 金额: $ 24.15万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8608502
• 关键词: Address; Adverse effects; Algorithms; Alleles; Benz(a)Anthracenes; Binding Sites; Boxing; Breast Cancer Cell; Breeding; Cancer Patient; Cancer cell line; Carcinogens; Cell Line; Cells; ChIP-seq; Complex; Coupled; DNA Methylation; Development; Disease; Epigenetic Process; Estrogen Antagonists; Estrogen Receptor alpha; Estrogens; Female; Gene Expression Profiling; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genomics; Goals; Growth; Hepatocarcinogenesis; Histones; Hormonal; Hormones; Human; In Vitro; Laboratories; Lead; Liver; Location; Malignant Neoplasms; Malignant neoplasm of liver; Mammary Neoplasms; Mammary gland; Maps; Mass Spectrum Analysis; Mediating; Medroxyprogesterone 17-Acetate; Messenger RNA; Modeling; Mouse Mammary Tumor Virus; Mus; Mutant Strains Mice; Nature; Nucleosomes; Primary carcinoma of the liver cells; Proteins; Proteomics; Protocols documentation; RNA Interference; Regulation; Signal Transduction; Technology; Testing; Therapeutic; Therapeutic Studies; Tissues; Toxic effect; abstracting; benzanthracene; cancer genomics; cancer therapy; carcinogenesis; comparative genomics; epigenomics; functional genomics; genome wide association study; genome-wide; hormone related cancer; human cancer mouse model; human tissue; in vivo; in vivo Model; loss of function; malignant breast neoplasm; mouse model; new therapeutic target; overexpression; prevent; receptor; stem cell differentiation; success; therapeutic target; transcription factor; tumor growth; tumor progression

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).

项目总结/摘要 癌症是最令人绝望的疾病之一，由于其治疗的有限成功。然而，大自然 已经为治疗癌症提供了线索，特别是与性行为有关的癌症，如肝癌和乳腺癌。 癌雌激素，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），表明我们可能使用来自一种癌症的信息 治愈另一种癌症体外研究表明，通过雌激素受体α（ER <$）的雌激素信号传导， 促进乳腺癌细胞的生长依赖于叉头盒蛋白A（Foxa）。我们最近发现， 雌激素预防肝癌还取决于体内Foxa因子。因此，我提出了一个比较 使用体内模型对肝癌和乳腺癌之间的Foxa/ER双靶点进行基因组学研究， 人癌组织和细胞，以解决癌症进展的机制，并鉴定新的 两种癌症的治疗靶点。首先，研究Foxa依赖的ER介导的 雌激素信号也促进乳腺肿瘤的生长，这还没有在体内研究过。我 本研究将利用Cre-loxP技术制备乳腺特异性Foxa 1/2缺陷小鼠， Foxa/ER <$dual regulations during carcinogenesis.功能基因组学分析，包括ChIP-Seq Foxa 1/2和ER？以及通过微阵列和mRNA-Seq进行的基因表达谱分析， Foxa/ER <$双重靶点促进乳腺癌。我们最近的研究还生成了一个Foxa/ER双 用同样的方法预防肝癌。第二，比较基因组学研究 将寻求肝癌和乳腺癌之间的Foxa/ER双重靶点，以确定新的治疗方法 针对这两种癌症的目标。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双靶点的组织差异调节表明， 第二层监管超越Foxa/ER？因此，蛋白质组学和表观基因组学的方法将被追求 在上述模型上发现Foxa/ER的组织特异性调节剂。这不仅能提供体内证据 癌症基因组学指导癌症治疗研究，但也将解决遗传和 表现/功能差异的相同转录因子的基因转录的表观遗传调节 在不同组织（肝脏与乳腺）或种属（小鼠与人）中。