CYCLIN D1 INDUCTION IN BREAST-CANCER CELLS SHORTENS G(1) AND IS SUFFICIENT FOR CELLS ARRESTED IN G(1) TO COMPLETE THE CELL-CYCLE

The sequential transcriptional activation of cyclins, the regulatory s ubunits of cell-cycle-specific kinases, is thought to regulate progres s through the cell cycle. Cyclins are therefore potential oncogenes, a nd cyclin D1 overexpression and/or amplification at its genomic locus, 11q13, are common features of several human cancers. Induction of cyc lin D1 is an early response to mitogenic stimulation in several cell t ypes, but the consequences of altered expression of this gene in human cells of epithelial origin remain undefined. We assessed the effects of alterations of cyclin D1 expression in human breast cancer cells by generating T-47D cells expressing human cyclin D1 under the control o f a zinc-responsive metallothionein promoter. In cycling cells inducti on of cyclin D1 after zinc treatment resulted in an increase in the nu mber of cells progressing through G(1) and in the rate of transition f rom G(1) to S phase, indicating that cyclin D1 is rate-limiting for pr ogress through G(1) phase, In cells arrested in early G(1) phase after growth factor deprivation, zinc induction of cyclin D1 was sufficient for completion of the cell cycle, a process requiring growth factor s timulation in control cells. These data demonstrate a critical role fo r cyclin D1 in human breast cancer cell-cycle control and suggest that deregulated expression of cyclin D1 is likely to reduce dependence on normal physiological growth stimuli, thereby providing a growth advan tage to tumor cells and a potential mechanism of resistance to endocri ne therapy.