Influence of chemopreventive agents on estradiol metabolism and mammary preneoplasia in the C3H mouse.

The C3H strain of mouse has a high incidence of murine mammary tumor virus-induced mammary tumors, and tumorigenesis progresses via the intermediate formation of the preneoplastic, hyperplastic alveolar nodules (HANs). The C3H mouse also exhibits an elevation in 16 alpha-hydroxylation of estradiol which remains unaltered in relation to the age or presence of tumor, but which is detectable well before the emergence of overt mammary cancer. This metabolic pathway leads to the formation of 16 alpha-hydroxyestrone (16 alpha-OHE1), a putative promoter of mammary cancer. The present study examines the effect of two prototype chemopreventive agents, tamoxifen (TAM) and N-(4-hydroxyphenyl)retinamide (HPR), on 16 alpha-hydroxylation of estradiol and on the growth of HANs. Treatment with TAM, HPR, or a combination of TAM and HPR for 4 weeks in 6- to 8-week-old C3H mice resulted in a consistent elevation in the 16 alpha-hydroxylation pathway of estradiol metabolism relative to the placebo control group (20.50% +/- 2.35%, 21.46% +/- 1.49%, 18.00% +/- 1.75%, and 12.64% +/- 1.45% SD, respectively) and in a significant decrease in the mean frequency of HANs per mammary gland (1.4, 2.1, 0.0, and 5.8, respectively). Mice without any experimental manipulation exhibited an age-dependent progressive increase in HAN frequency from 1.5 per gland at 4 weeks of age to 12.1 per gland at 24 weeks of age. Administration of TAM, HPR, or a combination of TAM and HPR up to 22 weeks of age resulted in a continued suppression of HAN frequency, and the two agents in combination exerted an additive effect on the suppression of HAN development.(ABSTRACT TRUNCATED AT 250 WORDS)