The specific objectives of this project include 1) to determine the analog and dose of retinoid that can prevent/delay mammary tumor development, 2) to determine the retinoid and tamoxifen combination effect on delaying mammary tumor development and 3) to determine the influence of type of diet and dietary ingredients in delaying the development of mammary tumors. For this purpose female transgenic (TG.NK) mice with human breast cancer oncogene """"""""neu"""""""" (erbB2) that develop 50% incidence of mammary tumors by 26 weeks of age were a) fed different diets to delay the development of tumors, b) treated with selected doses of retinoids to establish the most effective retinoid and dose and c) the most effective diet and retinoid analog will be further evaluated in combination with tamoxifen to determine the synergism between the diet and drugs. Retinyl acetate in diet delayed the development of mammry tumors in a dose response manner but may be toxic at the doses causing delay in tumor development. The experimental retinoid analog 4-hydroxyphenyl retinamide (4-HPR) when given in diet delayed the development of mammary tumors and showed a dose response at nontoxic doses. Another experimental retinoid analog Arotinoid Ro 40-8757 (Roche) caused a dose-related delay in development of mammry tumors but also caused dose-related toxicity. These results indicate that the transgenic TG.NK mouse model may be appropriate to evaluate intervention strategies to delay/prevent the development of breast cancer. About 50% of the TG.NK mice fed a purified diet AIN-76A containing 5% cellulose as fiber developed mammary tumors by 26-weeks of age. A Nonpurified diet NIH-07 with -3.5% active fiber (fiber that can bind estrogen and other substances) delayed the development of mammary tumors as compared to the purified diet. Another nonpurified diet NTP-2000 with lower protein and higher active fiber than NIH-07 diet markedly delayed the development of mammary tumors. These results indicate that increased fiber consumption appears to delay the development of mammary tumors in the TG.NK mouse model and the delaying effect of fiber was comparable to nontoxic doses of some retinoid analogs. This finding is in agreement with human epidemiological observations that higher fiber consumption may decrease the risk of breast cancer in women. The TG.NK model appears to be suitable for evaluation of intervention strategies such as diet, retinoid and tamoxifen combinations to prevent/delay breast cancer.
