Induction of mammary epithelial cell differentiation and inhibition of dimethylbenz(A)anthracene-induced mammary tumour by co-administration of a pure antiestrogen ICI 182,780 and testosterone enanthate

Epidemiological studies have shown that early first pregnancy is associated with a life-long reduction in breast cancer risk. The terminal differentia tion associated with pregnancy and lactation has been proposed as a mechani sm underlying the protective effect of pregnancy. We report that treatment of rats with ICI 182,780 (ICI) caused a marked reduction in epithelial cell s and Ki-67 labelling index as compared to controls and testosterone enanth ate-treated (TE) mammary glands. TE increased the Ki-67 labelling index, st imulated lobuloalveolar and ductal growth, as well as the secretory activit y of acinar cells. Go-administration of TE and ICI resulted in a reduction in Ki-67 labelling index. Mammary epithelial cells became differentiated, r esembling that observed at the end of pregnancy and during lactation as ind icated by marked increase in secretory activity, lipid accumulation and pre sence of basal nuclei. The expression of differentiation markers such as wh ey acidic protein, mammary derived growth inhibitor, a-casein and beta -cas ein was detected only in TE plus ICI treated mammary tissues. Unlike TE, IC I caused a significant reduction in DMBA-induced tumour incidence, number o f tumour bearing and tumour size. Tumour incidence was reduced to 8% when b oth ICI and TE were co-administered. Our data provide the novel molecular i nteractions between the estrogen and androgen in regulation of mammary grow th and differentiation. These observations may give insight into novel acti ons of ICI and TE on breast differentiation and protection against carcinog enesis which map be useful in designing novel strategies for cancer prevent ion and/or treatment based on maximizing mammary epithelial cell differenti ation.