Down-Regulation of Estrogen Receptors by Androgens in the ZR-75-1 Human Breast Cancer Cell Line*

Abstract

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.

Inhibition of MCF-7 breast cancer cell proliferation by 5alpha-dihydrotestosterone; a role for p21(Cip1/Waf1)

“…Androgens have been shown to induce antioestrogenic effects in breast cancer cells, principally by decreasing ER expression (Poulin et al 1989, Zhou et al 2000. However, growth suppression by androgens is thought to be additive to that of anti-oestrogens , suggesting that the steroids also induce changes independent from oestrogen responsiveness.…”

“…Although androgen-induced growth inhibition is associated with decreased ER expression (Poulin et al 1989, Zhou et al 2000, androgens have been shown to inhibit both basal and oestrogen-induced breast cancer cell proliferation (Poulin et al 1988, Zhou et al 2000 and their effects are additive to that induced by anti-oestrogens . These results indicate that androgens impede breast cancer cell proliferation by a mechanism in addition to reducing oestrogen responsiveness.…”

Sleep-disordered breathing and hormones

“…Androgens do not affect oestradiol or progesterone levels but may reduce their effect by downregulating oestrogen and progesterone receptors [132]. Oestrone levels increase with androgens [132].…”

Pushing estrogen receptor around in breast cancer

“…However, the prognosis of women with AR-positive breast cancer is exquisitely context dependent. When breast cancer is classified into molecular subgroups, AR expression is a consistent independent predictor of breast cancer survival only in the context of ER-positive disease (Luminal A and B subtypes) (Poulin et al 1989, Birrell et al 1998, Panet-Raymond et al 2000, Peters et al 2009, Castellano et al 2010, Park et al 2010. This reflects the anti-proliferative, anti-estrogenic influence of AR signalling in nearly all pre-clinical models of ER-positive breast cancer (Lanzino et al 2005) and the powerful ability of androgens to suppress ER-mediated growth of the normal mammary epithelium (Peters et al 2011).…”