Effects of alterations in early hormonal environment on development and hormone dependency of carcinogen-induced mammary tumors in rats

The purpose of this study was to determine the early role of estrogen and prolactin on subsequent hormone dependency of carcinogen-induced mammary tumors. Virgin 57-day-old Sprague-Dawley rats were given i.v. injections of 7,12-dimethylbenz(a)anthracene (DMBA). One day prior to and 7 days after DMBA administration, the rats were divided into separate groups and given: a daily 0.1-ml s.c. injection of vehicle (controls); haloperidol (0.5 mg/kg) to increase prolactin secretion; estradiol benzoate (1 microgram/rat) to increase estrogen levels; bromocryptine (5 mg/kg) to inhibit prolactin release; tamoxifen (TAM, 20 micrograms/rat) to inhibit estrogen action; or the combination of TAM and bromocryptine. Drug and hormone treatments were terminated after 8 days. Sixteen weeks after DMBA administration, all animals were bilaterally ovariectomized, and 4 weeks later it was determined whether the mammary tumors were hormone dependent or independent. Treatment with TAM resulted in a significant reduction in incidence of mammary tumors, but also a 3-fold increase in the percentage of these tumors that showed hormone independence after ovariectomy as compared with that of control rats. Rats treated with the combination of TAM and bromocryptine also showed a significant reduction in tumor incidence and number, but a 5-fold greater percentage of hormone-independent tumors after ovariectomy. Rats given daily injections of haloperidol or estradiol benzoate showed only small differences in mammary tumor incidence or autonomy after ovariectomy, as compared with controls given injection vehicle alone. These results suggest that rats made deficient in estrogen and prolactin at the time of DMBA administration develop fewer tumors, but the tumors that develop are not dependent on these hormones for subsequent growth.