INHIBITION OF CYCLIN-D EXPRESSION IN HUMAN BREAST-CARCINOMA CELLS BY RETINOIDS IN-VITRO

Transfection and transgenic mouse experiments supported an oncogenic r ole for cyclin D1 in breast cancer, We recently reported that noninvas ive carcinoma ill situ lesions of the human breast overexpress cyclin D, suggesting that this molecular event may represent a valuable targe t for chemoprevention, The purpose of the present series of investigat ions vr as to identify agents which could reduce the cyclin D expressi on of breast cells, We report that 9-cis retinoic acid (9-cis RA) and all trans retinoic acid (tRA) inhibited the cyclin D1 and D3 expressio n levels of human MCF-7, ZR-75 and T-47D breast carcinoma cells in vit ro. Where detectable, similar trends were observed in the immortalized , HBL-100 and MCF-10A breast cell lines, Cyclin D2 was undetectable, T he effect of retinoids was both dose- and time-dependent, and correlat ed with altered cell cycle kinetics and proliferative status, Retinoid s were also found to inhibit the expression levels of other cell cycle related proteins, including Cdk2 and Cdk4, resulting in lower kinase activities, In contrast to other breast prevention studies? no synergi stic effect was observed with retinoids and tamoxifen. The data indica te that retinoids can potently reduce ca clin D expression levels in a variety of breast cell Lines in vitro, and suggest further considerat ion of this mechanism for the chemoprevention of breast cancer.