ANDROGENS INDUCE DIVERGENT PROLIFERATIVE RESPONSES IN HUMAN BREAST-CANCER CELL-LINES

Although the majority of primary human breast cancers express the andr ogen receptor (AR), the role of androgens in breast cancer growth and progression is poorly understood. We have investigated the effects of the naturally occurring androgen, dihydrotestosterone (DHT), and a syn thetic non-metabolizable androgen, mibolerone, on the proliferation of six human breast cancer cell lines. The anti-proliferative and prolif erative effects of androgens were only observed in cell lines that exp ressed the AR. Two of the AR-positive cell lines, T47-D and ZR-75-1 we re growth inhibited in the presence of either DHT or mibolerone, while the proliferation of MCF-7 and MDA-MB-453 cells was increased by both androgens. Go-incubation of cultures with 1 nM DHT and a 100-fold exc ess of the androgen receptor antagonist, hydroxyflutamide, resulted in reversal of both inhibitory and stimulatory effects of DHT on T47-D, MCF-7 and MDA-MB-453 cell proliferation, indicating that DHT action is mediated by the AR in these lines. Hydroxyflutamide only partially re versed the DHT-induced growth inhibition of ZR-75-1 cultures, which su ggests that growth inhibition of these cells may be mediated by non-AR pathways of DHT (or DHT metabolite) action. Mibolerone action on brea st cancer cell growth was similar to that of DHT, with the exception t hat growth stimulation of MCF-7 and MDA-MB-453 cells was only partiall y reversed in the presence of a 100-fold excess of hydroxyflutamide. A nandron, another androgen receptor antagonist, was able to reverse all inhibitory and stimulatory actions of the androgens. AR antisense oli gonucleotides reduced the level of immunoreactive AR expression in MDA -MB-453 and ZR-75-1 cells by more than 60%, but only reversed the grow th inhibitory action of mibolerone in ZR-75-1 cultures. The results su ggest that androgen action in breast cancer cell lines may not be sole ly mediated by binding of androgen to the AR. For example, metabolites of DHT with oestrogenic activity, or androgen binding to receptors ot her than the AR, may explain the divergent responses to androgens obse rved in different breast cancer cell lines.