Androgen and glucocorticoid receptor-mediated inhibition of cell proliferation by medroxyprogesterone acetate in ZR-75-1 human breast cancer cells.
Abstract
Medroxyprogesterone acetate (MPA) is a synthetic progestin, currently used in the adjuvant treatment of advanced breast cancer, which induces remission rates (30-40%) comparable to those obtained with other types of endocrine therapies. Since, in addition to its progestin-like action, MPA exhibits androgen- and glucocorticoid-like activities in other tissues, the present study was designed to assess the relative contribution of the different steroid receptor systems in the direct action of MPA on breast cancer cell growth, using the ZR-75-1 human mammary carcinoma cell line as an in vitro model. Unlike pure progestins, MPA potently inhibited the proliferation of ZR-75-1 cells in a concentration-dependent manner either in the presence or in the absence of estrogens, and the addition of insulin had only marginal effects on its growth-inhibitory activity. On the other hand, both hydroxyflutamide (OHF, a non-steroidal monospecific antiandrogen) and RU486 (a potent antiglucocorticoid and antiprogestin also endowed with antiandrogenic activity) competitively reversed MPA antiproliferative effects. MPA further decreased the growth of ZR-75-1 cells co-incubated with maximally inhibitory concentrations of either 5 alpha-dihydrotestosterone (DHT) or dexamethasone (DEX), although at about 300-fold higher MPA concentrations with DHT-treated than with DEX-treated ZR-75-1 cells, thus demonstrating a highly predominant androgenic effect. However, MPA had no effect on the growth of ZR-75-1 cells co-incubated with DHT and DEX simultaneously, thus supporting the predominant role of androgen and glucocorticoid receptors in MPA action. A 12-day preincubation of ZR-75-1 cells with increasing concentrations of MPA (10(-12) to 3 x 10(-6)M) decreased the specific uptake of [3H]estradiol (E2) by intact cell monolayers to the same extent as 10 nM DHT, an effect which was competitively blocked by the addition of OHF (3 microM). MPA action on ZR-75-1 cell growth also significantly differed from that of progestins in being additive to the inhibition of E2-stimulated growth by the steroidal antiestrogen ICI164384. The present data indicate that the main action of MPA on ZR-75-1 human breast cancer cell growth is due to its androgen receptor-mediated inhibitory action, while its glucocorticoid-like activity could play an additional role at high concentrations.
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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 [209]
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 [209]
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 [209]
Similar inhibitory effects were observed on the levels of ER mRNA measured by ribonuclease protection assay.
“Similar inhibitory effects were observed on the levels of ER mRNA measured by ribonuclease protection assay (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 [209]
A half-maximal effect of DHT on [3H]E2 uptake was observed at 70 pM.
“A half-maximal effect of DHT on [ 3 H]E 2 uptake was observed at 70 pm (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 [209]
MPA exerts androgenic inhibitory effects on growth of human breast cancer cells in vitro.
“MPA has in fact been clearly shown to exert androgenic inhibitory effects on the growth of human breast cancer cells in vitro (209, 231, 245), thus suggesting the role of AR in the beneficial effects of MPA in breast cancer in women (246, 247).”
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 [209]
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Self-citation
- Authors
- Poulin, R., Baker, D., Poirier, D., & Labrie, F.
- Affiliations
- Centre hospitalier de l'Université Laval (CA)
- ORCID
- Poirier, Donald
- Venue
- Breast Cancer Research and Treatment
- Published
- 1989-03
- Volume
- 13
- Issue
- 2
- Pages
- 161-172
- ISSN
- 0167-6806 (ISSN-L)
- 1573-7217
- OpenAlex
- W2064332615
- Cited by
- 83
- References
- 55
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 1 · 2020: 1 · 2019: 3 · 2016: 3 · 2013: 3 · 2012: 2
- FWCI
- 3.30
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Breast Cancer Research and Treatment (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Medical Research Council
- 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
- medroxyprogesterone acetate, androgen receptor, glucocorticoid receptor, breast cancer cell proliferation, ZR-75-1 cells, progestins, RU486, hydroxyflutamide, dihydrotestosterone, dexamethasone, estradiol uptake, endocrine therapy, antiproliferative activity
- MeSH terms
- Breast Neoplasms, Cell Division, Cell Line, Female, Humans, Medroxyprogesterone, Receptors, Adrenergic, Receptors, Glucocorticoid, Medroxyprogesterone Acetate
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