CYCLIN D1 AND THE ESTROGEN RECEPTOR IN BREAST DEVELOPMENT

描述：(申请人描述)适用于年龄在15岁至15岁之间的女性 54乳腺癌是最常见的癌症致死原因。这个 在过去的50年里，乳腺癌的死亡率一直保持稳定。 将促进乳腺癌有效治疗方法的发展。 通过更好地理解作为基础的细胞机制 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，核癌基因细胞周期蛋白D1 被过度表达了。细胞周期蛋白D1在小鼠乳腺上皮细胞中的作用 孕期发育。乳房上皮细胞和乳腺癌细胞的体外培养 在乳腺中，细胞周期蛋白D1是在分化过程中被诱导的。在……里面 体外研究表明，在缺乏雌二醇的情况下，转录 内质网的功能是在分化过程中诱导的，这种诱导 与细胞周期蛋白D1水平的升高有关。这暗示了一种因果关系 这两个事件之间的关系。与此一致的是，细胞周期蛋白D1可以 结合内质网并激活其转录功能。 这一建议旨在更好地了解细胞周期蛋白D1在细胞周期中的作用。 乳房与内质网和细胞周期蛋白依赖性激酶4的关系。 细胞周期蛋白D1和内质网之间的相互作用将在 分子水平通过详细的遗传和生化分析。方法 将开发用于检测Cyclin D1-ER复合体的方法 乳腺上皮细胞或过表达细胞周期蛋白D1的细胞系中， 到目前为止只在体外观察到。我们将努力 了解细胞周期蛋白D1-ER相互作用的生物学意义。至 为此，研究了细胞周期蛋白D1功能的生物学意义 细胞周期蛋白D_1-ER的体外分化和基因解剖 将进行互动。这些研究的结果将使 细胞周期蛋白D1介导的内质网激活对BE的生理意义 在基因操纵的小鼠身上进行了测试。拟议工作的目标是 了解细胞周期蛋白D1如何激活内质网转录功能 并建立这种相互作用在乳腺上皮细胞中的生理作用 增殖、发育和/或肿瘤。

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.