Role of Cyclin D1 and cdk Inhibitors in Breast Cancer Pathogenesis

摘要

Cyclin Dl is frequently overexpressed in breast cancer tumors. Thus, an understanding of cyclin Dl regulation in normal and malignant cells may prove beneficial in the search for therapeutic targets. In fibroblastic cell lines, cyclin Dl expression is regulated by Rho/Rho kinase: (1) when Rho/Rho kinase is active, ERK activity is sustained and consequently cyclin Dl is induced in mid- G1 phase, and (2) when Rho/Rho kinase is inactive, cyclin Dl is induce in early G1 phase through a rac-mediated pathway (implicating PI-3 kinase signaling). In this report, I examined the consequences and regulation of rac-mediated cyclin Dl expression in terms of Rho kinase-dependent stress fiber formation. Selective inhibition of Rho kinase allowed for rac-mediated cyclin Dl expression, the downregulation of p21ci pl% %% and p27 kiPl and S phase entry, indicating that cell proliferation can occur under conditions where stress fiber formation is compromised. The suppression of the rac pathway to cyclin Dl expression by Rho kinase did not require stress fiber formation, indicating that there is a Rho kinase effector that has a role in cyclin Dl regulation without affecting actin reorganization. Future work includes the identification of this Rho kinase effector involved in the regulation of rac-mediated cyclin Dl expression.