Apoptosis, programmed cell death, is a normal physiological phenomenon that can be observed in various tissues. Since dysregulation of apoptosis can contribute to tumorigenesis, elucidation of nutritional and hormonal modulation of apoptotic pathways may contribute to prevention and therapeutic strategies. Thus, our goals are 1) to identify nutritional and hormonal factor(s) which modulate apoptotic pathways and 2) to investigate the mechanisms underlying this modulation. We have previously shown that the Bcl-2/Bax apoptotic pathways can be modulated by sex steroid hormone and dietary factors. Currently, we continued our investigation of modulation of apoptosis by dietary factors and chemopreventive agents. In collaboration with Dr. Steve Hursting of MD Anderson Cancer Center, Drs. James Phang and Susan Perkins of LNMR, we examined possible effects of chemopreventive regimen on apoptosis in mouse model. Using immunohistochemical detection we found that treatment with both dehydroepiandrosterone (DHEA) and calorie restriction (CR) resulted in decreased expression of the PCNA proliferation marker in the thymus of mices . In addition, treatment with DHEA also increased the rate of apoptosis in the thymus, resulting in marked thymic atrophy. Thus, both DHEA and CR appear to shift cell number homeostasis by favoring apoptosis. To further understand the molecular mechanisms by which DHEA and CR exert their effects, we examined two components of the apoptotic pathway, Bcl-2 and Bax. We found that p53-/- mice have much higher levels of Bcl-2 mRNA in the thymus than wild-type (p53+/+) mice. Treatment of p53-/- animals with DHEA resulted in decreased Bcl-2 but not Bax mRNA levels in the thymus. In contrast, CR did not change either Bcl-2 or Bax mRNA expression. These results provides molecular evidence that DHEA and CR may modulate tumorigenesis through alterations in the apoptotic and/or proliferative pathways.