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Developmental Endocrinology Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892, USA
1Correspondence: NICHD, NIH, Bldg. 10, Rm. 10N262, Bethesda, MD 20892, USA. E-mail: bondyc{at}exchange.nih.gov
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,
17ß 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 (ER
) mRNA expression by 50% (P<0.0001;
ERß 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 ER 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
ER 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.
Key Words: breast cancer • androgen • tamoxifen • monkey
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