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 differentiation associated with pregnancy and lactation has been proposed as a mechanism underlying the protective effect of pregnancy. We report that treatment of rats with ICI 182,780 (ICI) caused a marked reduction in epithelial cells and Ki-67 labelling index as compared to controls and testosterone enanthate-treated (TE) mammary glands. TE increased the Ki-67 labelling index, stimulated lobuloalveolar and ductal growth, as well as the secretory activity of acinar cells. Co-administration of TE and ICI resulted in a reduction in Ki-67 labelling index. Mammary epithelial cells became differentiated, resembling that observed at the end of pregnancy and during lactation as indicated by marked increase in secretory activity, lipid accumulation and presence of basal nuclei. The expression of differentiation markers such as whey acidic protein, mammary derived growth inhibitor, α-casein and β-casein was detected only in TE plus ICI treated mammary tissues. Unlike TE, ICI caused a significant reduction in DMBA-induced tumour incidence, number of tumour bearing and tumour size. Tumour incidence was reduced to 8% when both ICI and TE were co-administered. Our data provide the novel molecular interactions between the estrogen and androgen in regulation of mammary growth and differentiation. These observations may give insight into novel actions of ICI and TE on breast differentiation and protection against carcinogenesis which may be useful in designing novel strategies for cancer prevention and/or treatment based on maximizing mammary epithelial cell differentiation.