The effect of flutamide and tamoxifen on sex hormone-induced mammary carcinogenesis and pituitary adenoma

We have established a female Noble rat model to explore the mechanisms of hormonal mammary carcinogenesis. Based on the previous finding that the dose of testosterone affects only the latency period of mammary cancer, not the final incidence and that androgen upregulates apoptotic activity in pre-malignant mammary glands, we hypothesised that estrogen is the initiator and androgen the promoter for hormonal mammary carcinogenesis of the rats. In the present study, rats were treated with the sex hormones together with flutamide and tamoxifen for both short term (7 and 13 weeks) and long term (12 months) durations. We showed that tamoxifen could totally inhibit mammary carcinogenesis while flutamide cause a delay and reduction in tumour incidence in the 12 months treatment term. Blocking effect of flutamide and tamoxifen on T + E-2 (testosterone and 17beta-estradiol) short-terms treatment was demonstrated by the similar histological changes identified in the mammary glands of the T + E-2 and drug treated rats to that of the age matched E-2 and T controls, respectively. These findings give further support for the role of estrogen and androgen in mammary carcinogenesis. Autopsy of the tumour bearing rats showed presence of pituitary macroadenoma causing compression and atrophy of the brain stem. Immunohistochemical staining of these adenomas showed a predominance of prolactin-secreting cells. Serum assay also showed a corre-sponding increase in circulatory prolactin level. Tamoxifen was also effective in blocking the formation of pituitary adenoma in the sex hormone treated rats. Pituitary size and level of prolactin were higher in the T + E-2 +flutamide group than the T + E-2 group in both short-term and long-term treatments. It suggests that testosterone may have a role in counteracting estradiol stimulation on the pituitary lactotropes although it is synergistic to estrogen in mammary carcinogenesis. Pituitary adenomas were found in all rats that developed mammary adenocarcinoma but not vice versa suggesting that prolactin level elevation alone cannot lead to mammary tumorigenesis. The animal model, in addition to mammary carcinogenesis, may be useful for investigation of anti-estrogen therapy in pituitary adenomas.