Androgens inhibit basal and estrogen-induced cell proliferation in the ZR-75-1 human breast cancer cell line.
Abstract
This study describes the inhibitory effect of 5 alpha-dihydrotestosterone (5 alpha-DHT) and its precursors testosterone (T) and androst-4-ene-3,17-dione (delta 4-DIONE) on the growth of the estrogen-sensitive human breast cancer cell line ZR-75-1. In the absence of estrogens, cell proliferation measured after a 12-day incubation period was 50-60% inhibited by maximal concentrations of 5 alpha-DHT, T, or delta 4-DIONE with half-maximal effects (IC50 values) observed at 0.10, 0.15 and 15 nM, respectively. This growth inhibition by androgens was due to an increase in generation time and a lowering of the saturation density of cell cultures. The antiestrogen LY156758 (300 nM) induced 25-30% inhibition of basal cell growth, its effect being additive to that of 5 alpha-DHT. The mitogenic effect of 1 nM estradiol (E2) was completely inhibited by increasing concentrations of 5 alpha-DHT with a potency (IC50 = 0.10 nM) similar to that measured when the androgen was used alone. E2 had a more rapid effect on cell proliferation than 5 alpha-DHT, the latter requiring at least 5 to 6 days to exert significant growth inhibition. As found in the absence of estrogens, maximal inhibition of cell proliferation in the presence of E2 was achieved by the combination of the antiestrogen and 5 alpha-DHT. Supraphysiological concentrations of E2 (up to 1 microM) were needed to completely reverse the growth inhibitory effect of a submaximal concentration of 5 alpha-DHT (1 nM). The antiproliferative effect of androgens was competitively reversed by the antiandrogen hydroxyflutamide, thus indicating an androgen receptor-mediated mechanism. The present data suggest the potential benefits of an androgen-antiestrogen combination therapy in the endocrine management of breast cancer.
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The first demonstration of a potent and direct inhibitory effect of androgens on human breast cancer growth was obtained in the estrogen-sensitive human breast cancer cell line ZR-75-1.
“the first demonstration of a potent and direct inhibitory effect of androgens on human breast cancer growth was obtained in the estrogensensitive human breast cancer cell line ZR-75-1 (208).”
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 [208]
Our previous studies have clearly demonstrated that androgens exert a direct inhibitory effect on the proliferation of human breast cancer cells.
“our previous studies have clearly demonstrated that androgens exert a direct inhibitory effect on the proliferation of human breast cancer cells (208 -213).”
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 [208]
In ZR-75-1 cells, concentrations of DHT in the incubation medium similar to the plasma levels found in normal women and breast cancer patients (0.3-0.7 nM) are potent inhibitors of the mitogenic effect of E2 and even inhibit growth in the absence of estrogens.
“In ZR-75-1 cells, concentrations of DHT in the incubation medium similar to the plasma levels found in normal women (215-217) and breast cancer patients (Ref.218; 0.3-0.7 nm) are potent inhibitors of the mitogenic effect of E 2 and even inhibit growth in the absence of estrogens (208).”
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 [208]
In ZR-75-1 cells, DHT not only completely blocked the stimulatory effect of E2 on cell proliferation but also reduced cell growth in the absence of estrogens.
“DHT not only completely blocked the stimulatory effect of E 2 on cell proliferation but also reduced cell growth in the absence of estrogens.”
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 [208]
The effect of androgens on ZR-75-1 cell proliferation cannot be solely explained by the suppression of ER expression, because androgens still exert very potent inhibitory effects on growth in the absence of estrogens, even after prolonged periods of estrogen deprivation before exposure to androgens.
“The effect of androgens on ZR-75-1 cell proliferation, however, cannot be solely explained by the suppression of ER expression, because androgens still exert very potent inhibitory effects on growth in the absence of estrogens, even after prolonged periods of estrogen deprivation before exposure to androgens (208,211).”
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 [208]
The antiproliferative activity of androgens in estrogen-deprived ZR-75-1 cells is more pronounced and is additive to that exerted by antiestrogens.
“Moreover, the antiproliferative activity of androgens in estrogen-deprived ZR-75-1 cells is more pronounced and is additive to that exerted by antiestrogens (208,241).”
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 [208]
The data summarized above clearly support the hypothesis that at least part of the antagonism observed between the action of androgens and estrogens in breast cancer cells may be explained by the heterologous downregulation of the ER by an AR-mediated mechanism.
“The data summarized above clearly support the hypothesis that at least part of the antagonism observed between the action of androgens and estrogens in breast cancer cells (208,211,215,240) may be explained by the heterologous downregulation of the ER by an AR-mediated mechanism.”
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 [208]
Androgens act directly at the tumor level in DMBA-induced mammary carcinoma.
“suggested an action exerted directly at the tumor level, thus further supporting in vitro data obtained with the human ZR-75-1 breast cancer cell line (208,209).”
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 [208]
Androgens are potent inhibitors of DMBA-induced mammary carcinoma growth by an action independent from inhibition of gonadotropin secretion.
“Such data demonstrated, for the first time, that androgens are potent inhibitors of DMBA-induced mammary carcinoma growth by an action independent from inhibition of gonadotropin secretion and suggested an action exerted directly at the tumor level, thus further supporting in vitro data obtained with the human ZR-75-1 breast cancer cell line (208,209).”
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 [208]
The inhibitory effect of androgens on growth of ZR-75-1 human breast carcinoma cells is additive to that of an antiestrogen.
“Poulin et al. (208) have found that the inhibitory effect of androgens on the growth of ZR-75-1 human breast carcinoma cells is additive to that of an antiestrogen.”
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 [208]
In vitro studies provided the first demonstration of direct antiproliferative activity of androgens on growth of human mammary carcinoma cells using ZR-75-1 as model.
“in vitro studies have provided the first demonstration of the direct antiproliferative activity of androgens on the growth of human mammary carcinoma cells using the cell line ZR-75-1 as model (208, 253).”
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 [208]
DHT exerts a potent inhibitory effect on breast cancer cell proliferation in ZR-75-1 human breast cancer cells.
“DHT exerts a potent inhibitory effect on breast cancer cell proliferation in ZR-75-1 human breast cancer cells (208, 210)”
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 [208]
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Self-citation
- Authors
- Poulin, R., Baker, D., & Labrie, F.
- Affiliations
- Université Laval (CA)
- Venue
- Breast Cancer Research and Treatment
- Published
- 1988-10
- Volume
- 12
- Issue
- 2
- Pages
- 213-225
- ISSN
- 0167-6806 (ISSN-L)
- 1573-7217
- OpenAlex
- W2076033558
- Cited by
- 172
- References
- 58
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 1 · 2019: 4 · 2018: 5 · 2017: 8 · 2016: 7 · 2015: 2 · 2014: 5 · 2013: 5 · 2012: 4
- FWCI
- 4.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Breast Cancer Research and Treatment (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Terry Fox Foundation
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Keywords
- androgens, dihydrotestosterone, testosterone, androstenedione, breast cancer, ZR-75-1 cells, estrogen-induced cell proliferation, antiestrogens, hydroxyflutamide, androgen receptor, endocrine therapy
- MeSH terms
- Androgen Antagonists, Androstenedione, Breast Neoplasms, Cell Division, Cell Line, Dose-Response Relationship, Drug, Estradiol, Estrogen Antagonists, Flutamide, Humans, Piperidines, Receptors, Androgen, Receptors, Estrogen, Dihydrotestosterone, Testosterone, Raloxifene Hydrochloride
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