Dietary energy restriction (DER) has long been known to strikingly inhibit
carcinogenesis in many animal models. The animal data has been corroborated by recent and ongoing epidemiological studies demonstrating the importance of energy balance, physical exercise and
obesity in human
cancer. Dr. Edward Bresnick provided key insights into this important area of research and pivotal direction for the author's research while he served as Director of the Eppley Institute for Research in
Cancer, Omaha, NE. These insights moved this research toward demonstrating that DER reduced the expression of key
protein kinase C isoforms in mouse skin. More recent studies have uncovered downstream events that are inhibited by DER including blockage of
tumor promoter activation of Raf-1, ERK 1,2 and
AP-1 expression. Parallel studies have demonstrated the DER inhibition of these key cellular signaling events in mouse skin
carcinogenesis are dependent upon an intact adrenal gland because adrenalectomized mice fed DER diet did not have reduced
tumor burden or inhibited signaling and blocked
AP-1 activation as was observed in DER mice with intact adrenal glands. In addition, the DER inhibition of
tumorigenesis and
AP-1 signaling was restored in adrenalectomized mice that were given
corticosterone in the
drinking water. This showed that in mice in the chemical
carcinogenesis protocol
glucocorticoid hormone plays a major role in mediating DER prevention of
cancer. Studies are ongoing to further assess the mechanism of DER modulation of
skin cancer by assessing impacts on transcriptional regulation and expression of genes that are critical in skin
carcinogenesis.