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，美国乳腺癌新发病例的数量每年增加约1%。2007年，仅在美国，预计就有212，000例新的浸润性乳腺癌病例发生在女性和男性中。虽然乳腺癌目前是密集研究的主题，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定类型癌症的发展和治疗知之甚少。雌激素刺激表达雌激素受体的最常见类型的人类乳腺癌的增殖？(ER?)通过转录基因激活，将ER？在乳腺癌的发展中处于关键地位。虽然一个重要的机构的研究ER？尽管已经进行了多年，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？辅因子，由核LIM辅因子环指LIM结构域结合蛋白（RLIM）和LIM同源域转录因子（CLIM）的辅因子组成，其与ER？在乳腺癌细胞中。此外，我们的研究结果显示，CLIM高表达与人类患者中ER/PR阳性乳腺癌高度显著相关。我们假设LIM辅因子RLIM和CLIM决定性地调节ER？的生物活性。该建议旨在确定LIM辅因子1）在ER调节中的作用？- 介导的转录活性，2）已知的辅因子复合物的调节招募ER？3）对人乳腺癌和小鼠青春期后乳腺发育的意义。因此，拟议的研究将大大增加ER的知识？调节与乳腺癌的发展，从而可能解开新的策略，设计药物治疗乳腺癌患者的强烈影响。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。在这个应用程序中提出的实验将确定一组辅因子ER？关键调节其转录和生物活性，从而解开ER的新机制？调控预期的结果将导致新的策略设计的药物治疗乳腺癌。

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.