Testosterone inhibits estrogen-induced mammary epithelial proliferation and suppresses estrogen receptor expression

This study investigated the effect of sex steroids and tamoxifen on primate mammary epithelial proliferation and steroid receptor gene expression. Ova riectomized rhesus monkeys were treated with placebo, 17 beta estradiol (E2 ) alone or in combination with progesterone (E2/P) or testosterone (E2/T), or tamoxifen for 3 days. E2 alone increased mammary epithelial proliferatio n by similar to six-fold (P<0.0001) and increased mammary epithelial estrog en receptor (ER alpha) mRNA expression by similar to 50% (P<0.0001; ER beta mRNA was not detected in the primate mammary gland). Progesterone did not alter E2's proliferative effects, but testosterone reduced E2-induced proli feration by similar to 40% (P<0.002) and entirely abolished E2-induced augm entation of ER alpha expression. Tamoxifen had a significant agonist effect in the ovariectomized monkey, producing a similar to threefold increase in mammary epithelial proliferation (P<0.01), but tamoxifen also reduced ER a lpha expression below placebo level.. Androgen receptor (AR) mRNA was detec ted in mammary epithelium by in situ hybridization. AR mRNA levels were not altered by E2 alone but were significantly reduced by E2/T and tamoxifen t reatment. Because combined E2/T and tamoxifen had similar effects on mammar y epithelium, we investigated the regulation of known sex steroid-responsiv e mRNAs in the primate mammary epithelium. E2 alone had no effect on apolip oprotein D (ApoD) or IGF binding protein 5 (IGFBP5) expression, but E2/T an d tamoxifen treatment groups both demonstrated identical alterations in the se mRNAs (ApoD was decreased and IGFBP5 was increased). These observations showing androgen-induced down-regulation of mammary epithelial proliferatio n and ER expression suggest that combined estrogen/androgen hormone replace ment therapy might reduce the risk of breast cancer associated with estroge n replacement. In addition, these novel findings on tamoxifen's androgen-li ke effects on primate mammary epithelial sex steroid receptor expression su ggest that tamoxifen's protective action on mammary gland may involve andro genic effects.