Role of Cyclin D1 and cdk Inhibitors in Breast Cancer Pathogenesis
Annual rept. 30 Sep 1999-29 Sep 2000
PENNSYLVANIA UNIV PHILADELPHIA
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Extensive molecular, biochemical, cell biological, and cytogenetic studies of breast cancer cell lines and breast cancer biopsies have indicated that overexpression of cyclin Dl plays an important role in breast tumor oncogenesis. Particularly, D-type cyclins are fundamental to cell cycle regulation of the tumor suppressor protein, Rb. However, cyclin Dl has been reported being overexpressed to the same degree in both the early and late stages of breast cancer. Therefore, cyclin Dl overexpression alone may not be a good indicator of breast cancer. Preliminary data from our laboratory suggest that the cdk inhibitor p21cipl can be upregulated bycyclin Dl overexpression in NIH3T3. Also, we are examining the role of PI3K pathway in cell cycle progression given its relevance in cyclin Dl expression and its correlation with the tumor supressor gene, PTEN. We show in MEFs that LY294OO2 LY, a PI3K inhibitor, is able to reduce cyclin Dl expression level and to block entry in S phase with little effect on the level of the cdk inhibitors, p2l and p27. However, overexpression of cyclin Dl is not sufficient to restore cyclin A expression in cells treated with LY. Lastly, we found that cdk2 kinase activity was rescued in p27-null MEFs treated with LY. However, cyclin A induction was still completely abolished suggesting that another mechanism controlled by PI3K, together with p27 downregulation, needs to be active in order to allow the transition from Gl to S phase.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research