CYCLIN D1 AND THE ESTROGEN RECEPTOR IN BREAST DEVELOPMENT

描述：（申请人的描述）对于年龄在15岁和 54乳腺癌是癌症导致死亡的最常见原因。的 乳腺癌的死亡率在过去50年中保持稳定。 这将有助于开发有效的乳腺癌治疗方法 通过对细胞机制的进一步理解， 正常乳腺上皮细胞的增殖和分化。 在许多雌激素受体（ER）阳性的癌症中，细胞核癌基因细胞周期蛋白D1 是过度表达的细胞周期蛋白D1对小鼠乳腺上皮细胞增殖和分化的影响 怀孕期间的发育。在体外乳腺上皮细胞和 在体内乳腺细胞周期蛋白D1在分化过程中被诱导。在 体外研究表明，在没有雌二醇的情况下， ER的功能在分化过程中被诱导， 与细胞周期蛋白D1水平的增加相关。这表明了一种因果关系 这两个事件之间的关系。与此一致，细胞周期蛋白D1可以 与ER结合并激活其转录功能。 该建议旨在更好地理解细胞周期蛋白D1在细胞周期调控中的作用。 乳腺癌，无论是在其关系的ER和细胞周期蛋白依赖性激酶4。的 细胞周期蛋白D1和ER之间的相互作用将在 通过详细的遗传和生化分析，在分子水平上进行检测。方法 将被开发用于检测细胞周期蛋白D1-ER复合物， 乳腺上皮细胞或过表达细胞周期蛋白D1的细胞系， 迄今为止仅在体外观察到。将努力 了解cyclin D1-ER相互作用的生物学意义。到 为此，对细胞周期蛋白D1功能的生物学重要性进行了研究， 在体外分化和细胞周期蛋白D1-ER的遗传解剖过程中， 将进行互动。这些研究的结果将使 细胞周期蛋白D1介导的雌激素受体激活的生理意义 在基因操作的老鼠身上进行了测试。拟议工作的目标是 了解细胞周期蛋白D1如何激活ER的转录功能， 并确定这种相互作用在乳腺上皮细胞中的生理作用， 增殖、发育和/或瘤形成。

DESCRIPTION: (Applicant's Description) For women between the ages of 15 and 54 breast cancer is the most common cause of death due to cancer. The mortality rates for breast cancer have remained stable for the last 50 years. The development of effective treatments for breast cancer would be facilitated by an improved understanding of the cellular mechanisms that underlie the proliferation and differentiation of normal mammary epithelial cells. In many estrogen receptor (ER)-positive cancers the nuclear oncogene cyclin D1 is overexpressed. Cyclin D1 is essential for murine breast epithelial cell development during pregnancy. Both in vitro in breast epithelial cells and in vivo in the mammary gland cyclin D1 is induced during differentiation. In vitro studies suggest that, in the absence of estradiol, the transcriptional functions of the ER are induced during differentiation and this induction correlates with the increase in cyclin D1 levels. This suggests a causal relationship between these two events. Consistent with this, cyclin D1 can bind to the ER and activate its transcriptional functions. This proposal is aimed at better understanding the role of cyclin D1 in the breast, both in its relationship to the ER and cyclin-dependent kinase 4. The interaction between cyclin D1 and the ER will be characterized at the molecular level through a detailed genetic and biochemical analysis. Methods will be developed to detect cyclin D1-ER complexes in either differentiating breast epithelial cells or in cell lines which overexpress cyclin D1, which has hitherto been observed only in vitro. An effort will be made to understand the biological significance of the cyclin D1-ER interaction. To this end, an investigation of the biological importance of cyclin D1 function during in vitro differentiation and a genetic dissection of the cyclin D1-ER interaction will be undertaken. The results of these studies will enable the physiological significance of cyclin D1-mediated activation of the ER to be tested in genetically manipulated mice. The objective of the proposed work is to understand how cyclin D1 activates the transcriptional functions of the ER and to establish a physiologic role of this interaction in breast epithelial proliferation, development and/or neoplasia.