Roles of LIM cofactors for regulating ERalpha during oncogenesis and development

LIM 辅助因子在肿瘤发生和发展过程中调节 ERα 的作用

• 批准号: 8242872
• 负责人: INGOLF M BACH
• 金额: $ 32.71万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242872
• 关键词: Address; Affect; Binding Proteins; Biochemical Genetics; Biological; Biological Assay; Breast Cancer Cell; Cancer Patient; Cancer Prognosis; Cell Culture Techniques; Cells; Complex; Data; Development; Dominant-Negative Mutation; Drug Design; Estrogen Receptor 1; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Fingers; Gene Activation; Gene Targeting; Genes; Genetic Transcription; Human; Human Development; Knock-out; Knowledge; LIM Domain; Lead; MCF7 cell; Malignant Neoplasms; Mammary gland; Maps; Mediating; Medical; Molecular; Mus; Nuclear; Oncogenic; Pathway interactions; Patients; Positioning Attribute; Proteins; Puberty; Publishing; Recruitment Activity; Regulation; Reporting; Research; Role; Signal Pathway; Tertiary Protein Structure; Testing; Tissue Microarray; Transcriptional Activation; Transcriptional Regulation; Ubiquitin; United States; Woman; Work; cancer type; chromatin immunoprecipitation; cofactor; homeodomain; human RBX1 protein; in vivo; malignant breast neoplasm; mammary gland development; men; mouse model; multicatalytic endopeptidase complex; novel strategies; overexpression; promoter; protein complex; protein expression; research study; therapy development; transcription factor; tumor; tumorigenesis; ubiquitin ligase

DESCRIPTION (provided by applicant): The number of new cases of breast cancer has increased by about one percent per year in the United States since the 1940s. For 2007, an estimated 212,000 new cases of invasive breast cancer are expected to occur among women and men in the United States alone. Although breast cancer is currently subject of intense research an estimated 45,000 patients in the United States will still die from this type of tumour in 2007, demonstrating how little is known about the development and treatment of this particular type of cancer. Estrogen stimulates the proliferation of the most common type of human breast cancer that expresses estrogen receptor 1 (ER1) via transcriptional gene activation, placing ER1 in a key position for the development of breast cancer. Although a significant body of research on ER1 has been carried out over the years, the knowledge of its transcriptional mechanisms remains limited. In our preliminary experiments we have discovered a new set of cofactors for ER1, consisting of the nuclear LIM cofactors RING finger LIM domain-binding protein (RLIM) and cofactor of LIM homeodomain transcription factors (CLIM), that associate with and are able to modulate the transcriptional activity of ER1 in breast cancer cells. Furthermore, our results show a highly significant correlation of high CLIM expression with ER/PR positive breast cancers in human patients. We hypothesize that LIM cofactors RLIM and CLIM decisively regulate the biological activity of ER1. This proposal sets out to establish the roles of LIM cofactors 1) for the regulation of ER1-mediated transcriptional activity, 2) the regulation of known cofactor complexes recruited by ER1 and 3) the significance for human breast cancer as well as for mammary gland development following puberty in mice. Thus, the proposed research will greatly add to the knowledge of ER1 regulation with strong implications for the development of breast cancer thereby likely unraveling new strategies for the design of drugs to treat breast cancer patients. Narrative Estrogen receptor ? (ER?) is decisively involved in the development of many human breast cancers. The proposed experiments in this application will identify a set of cofactors for ER? that critically regulates its transcriptional and biological activity, thereby unravelling new mechanisms of ER? regulation. The expected results will lead to novel strategies for the design of drugs against breast cancer.

描述（由申请人提供）：自 20 世纪 40 年代以来，美国新发乳腺癌病例数量每年增加约 1%。 2007 年，预计仅在美国女性和男性中就会出现 212,000 例新的浸润性乳腺癌病例。尽管乳腺癌目前是深入研究的主题，但估计 2007 年美国仍有 45,000 名患者死于这种类型的肿瘤，这表明人们对这种特殊类型癌症的发展和治疗知之甚少。雌激素通过转录基因激活刺激表达雌激素受体1（ER1）的最常见人类乳腺癌类型的增殖，使ER1处于乳腺癌发生的关键位置。尽管多年来对 ER1 进行了大量研究，但对其转录机制的了解仍然有限。在我们的初步实验中，我们发现了一组新的 ER1 辅助因子，由核 LIM 辅助因子 RING Finger LIM 结构域结合蛋白 (RLIM) 和 LIM 同源域转录因子 (CLIM) 辅助因子组成，它们与乳腺癌细胞中 ER1 的转录活性相关并能够调节。此外，我们的结果显示，人类患者中 CLIM 高表达与 ER/PR 阳性乳腺癌存在高度显着相关性。我们假设 LIM 辅因子 RLIM 和 CLIM 决定性地调节 ER1 的生物活性。该提案旨在确定 LIM 辅因子的作用：1）调节 ER1 介导的转录活性，2）调节 ER1 募集的已知辅因子复合物，以及 3）对人类乳腺癌以及小鼠青春期后乳腺发育的重要性。因此，拟议的研究将极大地增加对 ER1 调节的了解，对乳腺癌的发展具有重大影响，从而可能揭示设计治疗乳腺癌患者的药物的新策略。叙述 雌激素受体 ? （ER？）对许多人类的发展起着决定性的作用 乳腺癌。本申请中提出的实验将确定一组 ER 的辅助因子？严格调节其转录和生物活性， 从而揭示ER的新机制？规定。预期结果将引领 设计抗乳腺癌药物的新策略。