Apoptosis, programmed cell death, is a normal physiological phenomenon that can be observed in various tissues. Since deregulation of apoptosis can contribute to tumorigenesis, elucidation of nutritional modulation of the apoptotic pathways will contribute to cancer prevention and therapeutic strategies. Thus, our goals are 1) to identify nutritional and dietary factor(s) which modulate the apoptotic pathways and 2) to investigate the mechanisms underlying this modulation. The protein Bcl-2 has been shown to be a component of the apoptotic pathway. We have previously shown that exposure to 17beta-estradiol resulted in changes in Bcl-2 mRNA level in a time and concentration-dependent fashion,_while the Bax mRNA levels remained unchanged. In addition, pretreatment with 17 beta-estradiol protected MCF-7 cells from apoptosis. Our study suggests that the response of breast epithelial cells toward a steroid sex hormone involves regulation of apoptotic pathways. Currently, we are emphasizing the modulation of this pathway by dietary factors and chemopreventive agents. We observed that natural and synthetic retinoids exert differential effect on the Bcl-2/Bax apoptosis pathway. We found that in the estrogen receptor (ER) positive human breast cancer cell line MCF-7 but not in ER negative. MDA-MB-231 cells, the addition of 4-HPR, a synthetic retinoid with chemopreventive properties, resulted in concentration and time-dependent decreases in Bcl-2 mRNA levels. 4-HPR also effectively blocked the estradiol stimulated increase in Bcl-2 mRNA levels. Although 13-cis and all-trans retinoic acid were without effect on basal Bcl-2 mRNA levels, they did abolish the estradiol stimulation of Bcl-2 mRNA level. No effect was observed for retinol. We also examined the effect of 4-HPR on apoptosis. Among the retinoids tested, 4-HPR was unique in its ability to increase apoptosis. This effect was seen in both ER positive MCF-7 cells and ER negative MDA-MB-231 cells. We concluded that 4-HPR increases apoptosis by both ER dependent and independent mechanism. The ER-dependent mechanism in MCF-7 involves modulation of Bcl-2 expression. The underlying mechanisms of these effects are being studied in detail.
