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Influence of Caffeine on Development of Benign and Carcinomatous Mammary Gland Tumors in Female Rats Treated with the Carcinogens 7,12-Dimethylbenz(a)anthracene and N-Methyl-N-nitrosourea¹

Departments of Pharmacology and Toxicology [L. C. V., C. W. W.] and Anatomy [D. M. W.], Michigan State University, East Lansing, Michigan 48824

The effect of chronic caffeine consumption (500 mg/liter of drinking water) on the initiation and promotion stages of 7,12-dimethylbenz(a)anthracene (DMBA) (a low dose, 0.5 mg/100 g body weight, i.v.) and N-methyl-N-nitrosourea (MNU) (a standard dose, 2.5 mg/100 g body weight, i.v.) induced mammary gland tumorigenesis in female Sprague-Dawley rats was determined. In the initiation studies, caffeine was administered for 30 days prior to and for 3–4 days after carcinogen treatment (carcinogens administered at 55–57 days of age); in the promotion studies, caffeine was administered beginning 3–4 days after carcinogen treatment and until experiment termination (DMBA study and MNU study, 48 and 26 weeks after carcinogen treatment, respectively). In the DMBA study, there were 62–73 rats/group, in the MNU study, 40 rats/group. Eighty-nine% of the mammary tumors induced by DMBA were benign (adenomas, fibroadenomas, often with cystic secretory activity), 11% were carcinomas (intraductal and invasive); virtually all of the MNU-induced mammary tumors were carcinomas (99%). Caffeine consumption during the initiation stage in the DMBA-treated rats resulted in a significant decrease in the mean number of mammary carcinomas per rat (50% reduction, P < 0.01) and mean number of benign mammary tumors per rat (28% reduction, P < 0.05); caffeine consumption during the promotion stage significantly decreased the mean number of benign mammary tumors per rat (57% reduction, P < 0.001) while not significantly influencing mammary carcinoma number. In contrast, caffeine consumption during either the initiation or promotion stages of MNU-treated rats did not significantly influence this tumorigenic process. The influence of caffeine on urinary and fecal excretion of tritiated DMBA and on rat mammary gland development at the time of carcinogen treatment also was determined. Slightly reduced levels of tritium in 24-h urinary samples were observed in caffeine-treated animals (P = 0.06). No significant effect of caffeine on 24- to 96-h fecal or 48- to 96-h urinary excretion of the isotope was observed. No apparent effect of caffeine on rat mammary gland development (number of ducts, degree of lobuloalveolar development) was observed. That caffeine significantly suppresses the initiation stage of DMBA-induced rat mammary gland tumorigenesis, while not influencing this stage when MNU is used as a carcinogen, suggests that caffeine acts via an alteration in carcinogen (DMBA) activation. The lack of a pronounced effect of caffeine on tritiated DMBA excretion, however, does cast some doubt on this mechanism. How caffeine inhibits the development of benign mammary tumors, when administered during the promotion stage, is not known and is currently under investigation.

¹ Research supported by NIH Research Grant CA-37613.

² To whom requests for reprints should be addressed, at Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824.

Received 11/14/90. Accepted 4/23/91.