MAMMARY-GLAND CARCINOGENICITY OF 2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE IN SPRAGUE-DAWLEY RATS ON HIGH-FAT AND LOW-FAT DIETS

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a carcinogen ic heterocyclic amine derived from cooked meat. Mammary gland tumors w ere induced in female Sprague-Dawley rats given 10 doses of PhIP (75 m g/kg po) once per day from 43 days of age and then placed on a defined high-fat (23.5% corn oil) or low-fat (5% corn oil) diet for 25 weeks. Mammary tumor incidence was 49% (44 of 90 rats) and 31% (27 of 88 rat s) in the high- and low-fat groups, respectively. No tumors were found in vehicle control rats on the high- or the low-fat diet (n = 44 and 43, respectively). The higher tumor incidence in the high-fat group wa s due to an increase specifically in carcinomas (classified as tubulop apillary carcinomas) rather than benign tumors (tubular adenomas and f ibroadenomas). The incidence of carcinomas was 45% and 24% in PhIP-tre ated rats on the high- and low-fat diets, respectively. In addition, t he percentage of carcinomas showing stromal invasion was highest in th e high-fat diet group (22% vs. 8%, high- vs. low-fat diet). Proliferat ing cell nuclear antigen immunostaining (PCNA) index revealed six time s more proliferation in carcinomas from rats on the high-fat diet than in rats on the low-fat diet. Adenomas from rats on different diets ha d similar PCNA indexes. The tumor apoptotic index, quantitated by immu nohistochemical detection (terminal deoxynucleotidyl transferase nick end labeling), was twice as high in carcinomas from rats on the high-f at diet as in carcinomas from rats on the low-fat diet but was similar between the two groups of adenomas. The PCNA-to-apoptosis ratio was 4 3 and 17 in carcinomas from rats on the high- and low-fat diets, respe ctively, indicating that the growth rate of carcinomas was greater in rats on the high-fat diet. The results from this study show that the h igh-fat diet increases the incidence, invasiveness, and growth of PhIP -induced mammary gland carcinomas.