Testosterone inhibits estrogen-induced mammary epithelial proliferation and suppresses estrogen receptor expression.
Abstract
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, 17beta 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 approximately sixfold (P:<0.0001) and increased mammary epithelial estrogen receptor (ERalpha) mRNA expression by approximately 50% (P:<0.0001; ERbeta mRNA was not detected in the primate mammary gland). Progesterone did not alter E2's proliferative effects, but testosterone reduced E2-induced proliferation by approximately 40% (P:<0.002) and entirely abolished E2-induced augmentation of ERalpha expression. Tamoxifen had a significant agonist effect in the ovariectomized monkey, producing a approximately threefold increase in mammary epithelial proliferation (P:<0.01), but tamoxifen also reduced ERalpha 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.
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Treatment of ovariectomized monkeys with testosterone decreased by about 40% the stimulation of mammary epithelial proliferation induced by E2.
“treatment of ovariectomized monkeys with testosterone decreased by about 40% the stimulation of mammary epithelial proliferation induced by E 2 (200).”
From Endocrine and intracrine sources of androgens in women: inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone (2003) · cites this paper as [200]
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- Authors
- Zhou, J., Ng, S., Adesanya-Famuiya, O., Anderson, K., & Bondy, C. A.
- Affiliations
- National Institutes of Health (US)
- Developmental Endocrinology Branch NICHD National Institutes of Health Bethesda Maryland 20892 USA
- Corresponding author
- Bondy, Carolyn A.
- ORCID
- Zhou, Jian
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2000-09
- Volume
- 14
- Issue
- 12
- Pages
- 1725-1730
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2000766198
- Cited by
- 193
- References
- 31
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 7 · 2023: 2 · 2022: 4 · 2021: 9 · 2020: 2 · 2019: 3 · 2018: 2 · 2017: 3 · 2016: 6 · 2015: 5 · 2014: 12 · 2013: 6 · 2012: 9
- FWCI
- 6.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Keywords
- testosterone, estrogen receptor alpha, mammary epithelial cell proliferation, tamoxifen, androgen receptor, estradiol, progesterone, rhesus monkeys, apolipoprotein D, IGF binding protein-5, breast cancer risk, hormone replacement therapy, sex steroid receptors
- MeSH terms
- Animals, Cell Division, Drug Interactions, Epithelial Cells, Estradiol, Estrogen Antagonists, Estrogens, Female, Macaca mulatta, Progesterone, Receptors, Androgen, Receptors, Estrogen, Tamoxifen, Testosterone, Gene Expression
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