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. Ovariectomized rhesus monkeys were treated with placebo, 17β estradiol (E2) alone or in combination with progesterone (E2/P) or testosterone (E2/T), or tamoxifen for 3 days. E2 alone increased mammary epithelial proliferation by ~sixfold (P<0.0001) and increased mammary epithelial estrogen receptor (ERα) mRNA expression by ~50% (P<0.0001; ERβ mRNA was not detected in the primate mammary gland). Progesterone did not alter E2's proliferative effects, but testosterone reduced E2‐induced proliferation by —40% (P< 0.002) and entirely abolished E2‐induced augmentation of ERα expression. Tamoxifen had a significant agonist effect in the ovariectomized monkey, producing a ~threefold increase in mammary epithelial proliferation (P<0.01), but tamoxifen also reduced ERα expression below placebo level. Androgen receptor (AR) mRNA was detected 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 treatment. Because combined E2/T and tamoxifen had similar effects on mammary epithelium, we investigated the regulation of known sex steroid‐responsive mRNAs in the primate mammary epithelium. E2 alone had no effect on apolipoprotein D (ApoD) or IGF binding protein 5 (IGFBP5) expression, but E2/T and tamoxifen treatment groups both demonstrated identical alterations in these mRNAs (ApoD was decreased and IGFBP5 was increased). These observations showing androgen‐induced down‐regulation of mammary epithelial proliferation and ER expression suggest that combined estrogen/androgen hormone replacement therapy might reduce the risk of breast cancer associated with estrogen replacement. In addition, these novel findings on tamoxifen's androgen‐like effects on primate mammary epithelial sex steroid receptor expression suggest that tamoxifen's protective action on mammary gland may involve androgenic effects.— Zhou, J., Ng, S., Adesanya‐Famuiya, O., Anderson, K., Bondy, C. A. Testosterone inhibits estrogen‐induced mammary epithelial proliferation and suppresses estrogen receptor expression. FASEB J. 14, 1725–1730 (2000)

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