Roles of LIM cofactors for regulating ERalpha during oncogenesis and development

描述(申请人提供)：自20世纪40年代以来，美国乳腺癌的新病例数量以每年约1%的速度增长。2007年，仅在美国，估计就有21.2万例新的浸润性乳腺癌病例发生在女性和男性中。尽管乳腺癌目前是密集研究的对象，但据估计，2007年美国仍将有4.5万名患者死于这种类型的肿瘤，这表明人们对这种特殊类型的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)的最常见类型的乳腺癌的增殖，使ER1在乳腺癌的发展中处于关键地位。尽管多年来已经对ER1进行了大量的研究，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，包括核LIM辅助因子环指状LIM结构域结合蛋白(RLIM)和LIM同源结构域转录因子(CLIM)，它们与乳腺癌细胞中ER1的转录活性相关并能够调节其转录活性。此外，我们的结果显示，在人类患者中，CLIM的高表达与ER/PR阳性的乳腺癌存在高度显著的相关性。我们假设LIM辅助因子RLIM和CLIM对ER1的生物活性起决定性的调节作用。这项建议旨在确定LIM辅助因子的作用1)调节ER1介导的转录活性，2)调节ER1招募的已知辅助因子复合体，3)对人类乳腺癌以及小鼠青春期后乳腺发育的意义。因此，这项拟议的研究将极大地增加对ER1调控的了解，对乳腺癌的发生具有重要意义，从而可能为设计治疗乳腺癌患者的药物提供新的策略。叙述性 雌激素受体？(呃？)决定性地参与了许多人类的发展 乳腺癌。此应用程序中建议的实验将识别一组 ER的辅因子？对其转录和生物活性进行严格调控， 从而揭开内质网的新机制？监管。预期结果将领先 到针对乳腺癌的药物设计的新策略。

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 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.