Prostate cancer (PC) is a major, understudied and poorly understood geriatric problem. Its occurrence depends on the presence of androgens and has been associated with mutations in tumor suppressor genes. Epidemiologic data suggest that diet and serum androstenedione levels may influence the progression of latent forms of PC into more aggressive PC. One prospective study linked high androstenedione levels with the later development of PC. As for diet, Japanese and Americans show similar prevalences of latent PC but progression to clinical significance is rare in Japan. Yet, when Japanese migrate to the USA, an increased incidence of malignant PC occurs suggesting the possibility of dietary influences. A study in Lobund-Wistar (LW) rats which provides a model of spontaneous and metastatic PC supports a dietary role: a modest calorie restriction (30%) reduced PC incidence from 26% in controls to 6%. All rats ate low fat diet (5%) which is germane due to fat intake suggested as a risk factor. This result in LW rats agrees with a large literature showing that caloric restriction of rodents retards cancer and aging. Our broad goals are to elucidate molecular and cellular changes associated with PC development and to evaluate dietary influences on these events. Two hypotheses will be tested: 1) Plasma levels of androgens and/or prolactin (another important regulator of prostatic growth) and the level of prostate androgen receptor (AR) are risk factors for the development of PC; and, 2) Influences of diet and aging on PC are linked to the frequency of mutations in tumor suppressor genes and/or the AR gene. To test these, male LW rats will be fed a low fat (5%) diet ad lib until 12 mo old when they will be assigned to one of four diet groups (n=70-80) and fed purified diets designed to provide all rats with balanced intakes of protein, vitamins and minerals but differing in calorie and fat intakes: Group A) Normal Calorie/Low Fat (N/L); rats fed ad lib via a 5% fat (corn oil) diet; B) Normal Calorie/Medium Fat (N/M): ad lib via a 15% fat diet; C) Low Calorie/Medium Fat (L/M): gradually restricted to 60% of ad lib intake via a 15% fat, nutrient-enriched diet; D) Low Calorie/High Fat (L/H): gradually restricted to 60% of ad lib via a 30% fat, nutrient-enriched diet. Rats will be killed at 12 mo of age (baseline) and at 6 mo intervals thereafter over the life span.
The Specific Aims are to determine: 1) PC prevalence (via histopathology); 2) androgen and prolactin levels (via RIA) in serum; 3) AR levels (via flow cytometry) in normal prostate and in PC cells; and, 4) mutation frequency of tumor suppressor genes (RB and p53) and of the AR gene in PC cells (via Northern blot and polymerase chain reaction). The proposed studies will improve understanding of the pathogenesis of PC and the extent to which it is sensitive to diet. The data should aid in the development of preventive and therapeutic interventions to combat the alarming PC problem.
