Diet and cancer prevention studies in p53-deficient mice.
Progress in mechanism-based cancer prevention research may be facilitated by the use of animal models displaying specific genetic susceptibilities for cancer such as mice deficient in the p53 tumor suppressor gene, the most frequently altered gene in human cancer. We observed in p53-knockout (p53-/-) mice that calorie restriction (CR; 60% of the control group's intake of carbohydrate energy) increased the latency of spontaneous tumor development (mostly lymphomas) approximately 75%, decreased serum insulin-like growth factor (IGF)-1 and leptin levels, significantly slowed thymocyte cell cycle traverse and induced apoptosis in immature thymocytes. In heterozygous p53-deficient (p53+/-) mice, CR and 1 d/wk of food deprivation each significantly delayed spontaneous tumor development (a mix of lymphomas, sarcomas and epithelial tumors) and decreased serum IGF-1 and leptin levels even when begun late in life. We have also developed a rapid and relevant p53+/- mouse mammary tumor model by crossing p53-deficient mice with MMTV-Wnt-1 transgenic mice, and found that CR and 1 d/wk food deprivation significantly increased mammary tumor latency (greater than twofold) and reduced the mean serum IGF-1 and leptin levels to <50% of that of control mice (P < 0.0001). In addition, fluasterone, fenretinide and soy each delayed tumor development but had little effect on IGF-1 or leptin levels. We have capitalized on the susceptibility of p53+/- mice to chronic, low dose, aromatic amine-induced bladder carcinogenesis to develop a useful model for evaluating bladder cancer prevention approaches such as cyclooxygenase-2 inhibition. As demonstrated by these examples, mice with specific (and human-like) genetic susceptibilities for cancer provide powerful new tools for testing and characterizing interventions that may inhibit the process of carcinogenesis in humans.
Hursting
S D
SD
National Cancer Institute, Bethesda, MD 20892,USA. hursting@ncifcrf.gov
Perkins
S N
SN
Phang
J M
JM
Barrett
J C
JC
D000818:Animals; D003433:Crosses, Genetic; D004032:Diet; D004038:Diet, Reducing; D004195:Disease Models, Animal; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D020738:Leptin / Q000097:blood; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D009374:Neoplasms, Experimental / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control
D020738:Leptin; D016159:Tumor Suppressor Protein p53; D007334:Insulin-Like Growth Factor I