Cyclin D1 in Breast Development and Cancer

细胞周期蛋白D1在多种不同组织学来源的癌症中经常过表达，包括乳腺癌。然而，细胞周期蛋白D1的过度表达如何对乳腺癌的发展有实质性的贡献尚不清楚。已经描述了细胞周期蛋白D1的两种活性。其中之一，细胞周期蛋白D1与其催化伙伴cdk 4和cdk 6一起影响视网膜母细胞瘤蛋白pRb的活性。另一方面，cyclin D1在没有cdks参与的情况下影响许多转录因子的活性。最近，对数百例人类肿瘤标本中数千个基因表达模式的分析表明，过表达的细胞周期蛋白D1在人类癌症中参与了一个不依赖cdk的转录程序。此外，这些分析表明转录因子C/EBP参与了 在人类癌症中受细胞周期蛋白D1影响的基因的调节。拟议的研究的广泛目标是测试的假设，过度表达的细胞周期蛋白DI异常改变的分化程序的乳腺上皮细胞在C/EBP依赖的方式，它的能力，这样做的基础上，其致癌作用在乳腺。将努力了解细胞周期蛋白D1如何影响活动的C/EBP使用分子，遗传和生物化学方法。是否过表达的细胞周期蛋白D1，以类似的方式异常表达的C/EBP，不利地改变乳腺上皮细胞的分化程序将被确定。将尝试开发一个强大的细胞周期蛋白D 1依赖性转化试验，使用一个合作的癌基因。这些试验将用于评估细胞周期蛋白D1在体外和体内异常影响C/EBP_1活性对乳腺上皮细胞转化的贡献。

Cyclin D 1 is frequently overexpressed in several cancers of diverse histological origin including those of the breast. However, how the overexpression of cyclin D1 contributes materially to the development of breast cancer is not understood. Two activities have been described for cyclin D1. In one, cyclin D1 together with its catalytic partners, cdk4 and cdk6, affects the activity of the retinoblastoma protein, pRb. In the other, cyclin D 1 influences the activity of a number of transcription factors without the participation of cdks. Recently, analyses of the expression patterns of thousands of genes across hundreds of human tumor specimens suggest that overexpressed cyclin D 1 engages a cdk-independent transcriptional program in human cancer. Further, these analyses suggest the involvement of the transcription factor, C/EBP, in the regulation of the genes affected by cyclin D1 in human cancer. The broad objective of the proposed research is to test the hypothesis that overexpression of cyclin DI aberrantly alters the differentiation program of mammary epithelial cells in a C/EBP-dependent manner and that its ability to do so underlies its oncogenic actions in the mammary gland. An effort will be made to understand how cyclin D1 influences the activity of C/EBP using molecular, genetic and biochemical approaches. Whether overexpression of cyclin D1, in a manner similar to aberrant expression of C/EBP, adversely alters the differentiation program of mammary epithelial cells will be determined. An attempt to develop a robust cyclin D l-dependent transformation assays using a cooperating oncogene will be made. These assays will be used to assess the contribution of the ability of cyclin D1 to aberrantly influence the activity of C/EBP_ to the transformation of mammary epithelial cells both in vitro and in vivo.