Roles of LIM cofactors for regulating ERalpha during oncogenesis and development

描述（由申请人提供）：自20世纪40年代以来，美国乳腺癌新病例的数量每年增加约1%。2007年，估计仅在美国就会有212,000例新的浸润性乳腺癌病例发生在女性和男性中。尽管乳腺癌目前是研究的重点，但据估计，到2007年，美国仍将有45000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。雌激素刺激最常见的表达雌激素受体的人类乳腺癌的增殖？（ER?）通过转录基因激活，将ER？对乳腺癌的发展起着关键作用。尽管有大量关于急诊室的研究？虽然已经进行了多年，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ER？，由核LIM辅助因子RING finger LIM结构域结合蛋白（RLIM）和LIM同源结构域转录因子（CLIM）组成，它们与ER？在乳腺癌细胞中。此外，我们的研究结果显示，在人类患者中，高CLIM表达与ER/PR阳性乳腺癌具有高度显著的相关性。我们假设LIM辅助因子RLIM和CLIM对ER?的生物活性起决定性的调节作用。本提案旨在确立LIM辅助因子在ER调控中的作用。-介导的转录活性；2)内质网募集的已知辅因子复合物的调控3)对人类乳腺癌和小鼠青春期后乳腺发育的意义。因此，所提出的研究将大大增加对急诊室的认识。对乳腺癌发展有重大影响的调控因此很可能揭示出治疗乳腺癌患者的药物设计的新策略。公共卫生相关性：雌激素受体？（ER?）在许多人类乳腺癌的发展中起决定性作用。本应用程序中提出的实验将确定一组ER？关键调控其转录和生物活性，从而揭示ER的新机制？监管。预期的结果将导致设计抗乳腺癌药物的新策略。

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 ? (ER?) via transcriptional gene activation, placing ER? in a key position for the development of breast cancer. Although a significant body of research on ER? 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 ER?, 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 ER? 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 ER?. This proposal sets out to establish the roles of LIM cofactors 1) for the regulation of ER? -mediated transcriptional activity, 2) the regulation of known cofactor complexes recruited by ER? 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 ER? 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. PUBLIC HEALTH RELEVANCE: 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.