Cyclin D1 Regulation of Nuclear Receptor Function in Breast Ca.
细胞周期蛋白 D1 对乳腺细胞核受体功能的调节。
基本信息
- 批准号:7086868
- 负责人:
- 金额:$ 31.04万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-07-02 至 2009-04-30
- 项目状态:已结题
- 来源:
- 关键词:SCID mouseacetylationbiological signal transductionbreast neoplasmscell differentiationcell growth regulationcell surface receptorsclinical researchcyclinselectron microscopyfemalegene expressiongene mutationgenetically modified animalshuman tissuemicroarray technologymitochondrianeoplasm /cancer geneticsneoplastic cellneoplastic growthperoxisome proliferator activated receptorprotein protein interactionprotein structure functionreceptor expressiontissue /cell culture
项目摘要
DESCRIPTION (provided by applicant): The ErbB2 transmembrane receptor is overexpressed in approximately 30% of human tumors. Mammary gland targeted ErbB2 overexpression is sufficient for mammary tumorigenesis in vivo. The cyclin D1 gene product is overexpressed in 30-50% of human breast cancers. Cyclin D1 anti-sense blocks ErbB2-induced mammary tumor growth and cyclin D1 -/- mice are resistant to ErbB2-induced tumor growth. The PPARgamma nuclear hormone receptor inhibits cellular proliferation and promotes differentiation. Mutations, rearrangements and altered expression of PPARgamma have been identified in several cancers suggesting PPARgamma may function as a tumor suppressor. We have shown cyclin D1 inhibits PPARgamma differentiation function, transactivation and expression in cultured ceils. We have shown CD1 -/- mice have genetic and phenotypic changes reflecting increased PPARgamma expression and activity, implicating increased PPARgamma in the tumor-resistant phenotype. The current studies will determine the molecular mechanisms by which cyclin D1 inhibits PPARgamma signaling in vivo. We will use mammary gland-targeted inducible transgenics to identify the molecular mechanisms by which cyclin D1 regulates PPARgamma function and determine the role of PPARgamma as a mammary gland tumor suppressor in the context of ErbB2. These studies will:
1. Determine the mechanism by which cyclin D1 inhibits PPARgamma transactivation. The ability of cyclin D1 to inhibit a subset of PPARgamma coactivators will be determined. As PPARgamma is acetylated and the cyclin D1 HDAC recruitment domain governs PPARgamma repression, the role of PPARgamma acetylation in repression by cyclin D1 will be determined.
2. Determine the mechanisms by which cyclin D1 inhibits PPARgamma function and expression. Cyclin D1 blocks PPARgamma induced differentiation of fibroblasts to adipocytes. We will identify the domain of cyclin D1 regulating PPARgamma differentiation. Cyclin D1 regulation of PPARgamma will be assessed in CD-/- mice, cyclin E knockin-CD-/- mice and in ponasterone-inducible cyclin D1 anti-sense mice. Correlative expression studies of PPARgamma and cyclin D1 will be conducted in 'benign' breast disease and breast cancers.
3. Determine the role of PPARgamma as a tumor suppressor of ErbB2-induced mammary tumorigenesis. We will determine the functional interactions between ErbB2 and PPARgamma in cultured cells and in ponasterone-inducible mammary gland-targeted PPARgamma transgenic mice. The use of inducible transgenics will allow the determination of PPARgamma function during mammary tumor onset and progression. If PPARgamma is an inhibitor of ErbB2-induced tumorigenesis and PPARgamma tumor suppressor function involves cyclin D1 repression, these studies provide a rational basis for identifying agonists of this interaction for potential therapeutic applications. Moreover, if PPARgamma levels are decreased in precursor lesions of breast cancer, the studies of PPARgamma in benign breast disease may provide a predictor of breast cancer progression. The proposed studies therefore may have important translational implications.
描述(由申请人提供):ErbB2跨膜受体在大约30%的人类肿瘤中过表达。乳腺靶向ErbB2过表达足以在体内发生乳腺肿瘤。细胞周期蛋白D1基因产物在30-50%的人类乳腺癌中过度表达。Cyclin D1反义阻滞erbb2诱导的乳腺肿瘤生长,Cyclin D1 -/-小鼠对erbb2诱导的肿瘤生长具有抗性。pparγ核激素受体抑制细胞增殖,促进细胞分化。PPARgamma的突变、重排和表达改变已在几种癌症中被发现,这表明PPARgamma可能具有肿瘤抑制作用。我们发现cyclin D1在培养细胞中抑制PPARgamma的分化功能、转激活和表达。我们已经证明CD1 -/-小鼠具有反映PPARgamma表达和活性增加的遗传和表型变化,暗示PPARgamma在肿瘤抗性表型中增加。目前的研究将确定细胞周期蛋白D1在体内抑制PPARgamma信号的分子机制。我们将使用乳腺靶向诱导转基因来确定细胞周期蛋白D1调节PPARgamma功能的分子机制,并确定PPARgamma在ErbB2背景下作为乳腺肿瘤抑制因子的作用。这些研究将:
项目成果
期刊论文数量(0)
专著数量(0)
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RICHARD G PESTELL其他文献
RICHARD G PESTELL的其他文献
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$ 31.04万 - 项目类别:
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