Androgen receptor agonist activity of the synthetic progestin, medroxyprogesterone acetate, in human breast cancer cells.

Bentel, Jacqueline M; Birrell, Stephen N; Pickering, Marie A; Holds, Duncan J; Horsfall, David J; Tilley, Wayne D

doi:10.1016/s0303-7207(99)00109-4

Cited by 110Estrogen and related hormone effectsProstate Cancer Treatment and ResearchBreast Cancer Treatment Studies

Androgen receptor agonist activity of the synthetic progestin, medroxyprogesterone acetate, in human breast cancer cells.

Bentel, Jacqueline M, Birrell, Stephen N, Pickering, Marie A, Holds, Duncan J, Horsfall, David J, Tilley, Wayne D·1999·Molecular and Cellular Endocrinology

DOI 10.1016/s0303-7207(99)00109-4

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Abstract

Medroxyprogesterone acetate (MPA), which is frequently used as second line hormonal therapy for the treatment of metastatic breast cancer, binds with high affinity to the progesterone receptor (PR). However, the androgenic side-effects of MPA suggest that it may also activate androgen receptor (AR) regulated pathways. Treatment of the human breast cancer cell lines MDA-MB-453, ZR-75-1 and T47-D with high dose (100 nM) MPA resulted in 26-30% inhibition of cell growth, which was partially reversed by co-treatment with a 10-fold excess of the synthetic antiandrogen, anandron. Scatchard analysis demonstrated specific, high affinity (non-PR) binding of [3H]MPA to cytosols prepared from the PR-/AR+ MDA-MB-453 and PR+/AR+ ZR-75-1, but not the PR-/AR- BT-20 breast cancer cell lines. Competition of [3H]MPA binding to MDA-MB-453 cytosols by equimolar concentrations of androgens (5alpha-dihydrotestosterone (DHT), R1881) and the antiandrogen, anandron was consistent with binding of MPA to the AR. In ZR-75-1 cell cytosol fractions, DHT, R1881 and anandron only partially competed out [3H]MPA binding, suggesting that androgens displace [3H]MPA binding to AR but not to PR. Induction by MPA of AR transactivation was demonstrated in MDA-MB-453 and ZR-75-1 cells, and in the CV-1 cell line transfected with a full-length AR. In these cell lines the increased activity of the androgen responsive reporter gene (MMTV-CAT) by 1 nM MPA was fully (MDA-MB-453, CV-1) or partially (ZR-75-1) inhibited by co-culture with 1 microM anandron. These findings indicate that MPA is an AR agonist and suggest that the in vivo effects of MPA in breast cancer patients may in part be mediated by the AR.

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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 [245]

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Authors: Bentel, J. M., Birrell, S. N., Pickering, M. A., Holds, D. J., Horsfall, D. J., & Tilley, W. D.
Affiliations: Royal Perth Hospital (AU)
Flinders University (AU)
Corresponding author: Tilley, Wayne D
ORCID: Bentel, Jacqueline M
Birrell, Stephen N
Pickering, Marie A
Tilley, Wayne D
Venue: Molecular and Cellular Endocrinology
Publisher: Elsevier BV
Published: 1999-08
Volume: 154
Issue: 1-2
Pages: 11-20
ISSN: 0303-7207 (ISSN-L)
DOI: 10.1016/s0303-7207(99)00109-4
OpenAlex: W1971344086
Cited by: 110
References: 40
Citations by year: 2026: 2 · 2025: 2 · 2023: 1 · 2022: 3 · 2021: 1 · 2020: 2 · 2019: 3 · 2017: 3 · 2016: 3 · 2015: 6 · 2014: 4 · 2013: 9 · 2012: 7
FWCI: 2.64
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Molecular and Cellular Endocrinology (publishedVersion)
PubMed (publishedVersion)
Funders: Flinders Medical Centre Foundation
Ramaciotti Foundations
National Health and Medical Research Council
National 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: medroxyprogesterone acetate, androgen receptor, androgen receptor agonists, breast cancer, progesterone receptor, androgen receptor antagonists, androgen receptor transactivation, MDA-MB-453, ZR-75-1, BT-20, androgen binding, hormonal therapy side effects
MeSH terms: Androgen Antagonists, Androgens, Antineoplastic Agents, Binding, Competitive, Breast Neoplasms, Cell Division, Cytosol, Female, Gene Expression Regulation, Humans, Imidazoles, Progestins, Receptors, Androgen, Transcription, Genetic, Tritium, Tumor Cells, Cultured, Medroxyprogesterone Acetate, Imidazolidines

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Androgen receptor agonist activity of the synthetic progestin, medroxyprogesterone acetate, in human breast cancer cells.

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