Cyclin D1 in Breast Development and Cancer

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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.