Cell cycle deregulation in breast cancer: Insurmountable chemoresistance or Achilles' heel?

Deregulation of the G1 cyclin, cyclin E, has been shown to be both the most powerful predictor of prognosis in early stage breast cancer as well as a significant determinant of tumor aggressiveness. It may also contribute to treatment failure due to chemoresistance. Because some form of cell cycle deregulation is present in all malignant cells, increasing understanding of these processes is starting to provide new opportunities to overcome the cells' resistance mechanisms. One particular form of cyclin E deregulation, the generation of hyperactive low molecular weight isoforms, is especially intriguing. Because only tumor cells contain the machinery necessary to generate these isoforms, they not only provide a mechanism of targeting critical cell cycle events, but their presence may also provide both a means of increased specificity for targeting malignant cells, as well as an objective measure of response. This review describes the mechanisms of resistance to commonly used systemic therapies for the treatment of breast cancer, with particular respect to the role of the cell cycle. The mechanisms and effects of the deregulation of cyclin E in breast cancer are reviewed and novel approaches to circumventing chemoresistance through abrogation of the malignant cell cycle are proposed.