Down-regulation of estrogen receptors by androgens in the ZR-75-1 human breast cancer cell line.
Much clinical evidence indicates that androgens have beneficial effects in the treatment of breast cancer in women. Physiological concentrations of androgens strongly inhibit both basal and estrogen-induced cell proliferation in the human breast cancer cell line ZR-75-1 through their interaction with the androgen receptor. The present study shows that androgens strongly suppress estrogen receptor (ER) and progesterone receptor contents in this model, as measured by radioligand binding and anti-ER monoclonal antibodies. Similar inhibitory effects are observed on the levels of ER messenger RNA (mRNA) measured by ribonuclease protection assay. The androgenic effect is observed at subnanomolar concentrations of the nonaromatizable androgen 5 alpha-dihydrotestosterone, regardless of the presence of estrogens, and is competitively reversed by the antiandrogen hydroxyflutamide. Such data on ER expression provide an explanation for at least part of the antiestrogenic effects of androgens on breast cancer cell growth and moreover suggest that the specific inhibitory effects of androgen therapy could be additive to the standard treatment limited to blockade of estrogens by antiestrogens.
Poulin
R
R
Medical Research Council Group in Molecular Endocrinology, Laval University Medical Center, Quebec, Canada.
Simard
J
J
Labrie
C
C
Petitclerc
L
L
Dumont
M
M
Lagace
L
L
Labrie
F
F
D000728:Androgens / Q000494:pharmacology*; D001665:Binding Sites; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D004958:Estradiol / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007124:Immunoenzyme Techniques; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000728:Androgens; D011960:Receptors, Estrogen; D004958:Estradiol