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 5α-dihydrotestosterone (5α-DHT) and its precursors testosterone (T) and androst-4-ene-3,17-dione (Δ⁴-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 5α-DHT, T, or Δ⁴-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 5α-DHT. The mitogenic effect of 1 nM estradiol (E₂) was completely inhibited by increasing concentrations of 5α-DHT with a potency (IC₅₀ = 0.10 nM) similar to that measured when the androgen was used alone. E₂ had a more repid effect on cell proliferation than 5α-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 5α-DHT. Supraphysiological concentrations of E₂ (up to 1µM) were needed to completely reverse the growth inhibitory effect of a submaximal concentration of 5α-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.