Although the majority of primary human breast
cancers express the
androgen 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 synthetic non-metabolizable
androgen,
mibolerone, on the proliferation of six human
breast cancer cell lines. The anti-proliferative and proliferative effects of
androgens were only observed in cell lines that expressed the AR. Two of the AR-positive cell lines, T47-D and ZR-75-1 were 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. Co-incubation of cultures with 1 nM DHT and a 100-fold excess 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 reversed the DHT-induced growth inhibition of ZR-75-1 cultures, which suggests that growth inhibition of these cells may be mediated by non-AR pathways of DHT (or DHT metabolite) action.
Mibolerone action on
breast cancer cell growth was similar to that of DHT, with the exception that growth stimulation of MCF-7 and MDA-MB-453 cells was only partially reversed in the presence of a 100-fold excess of
hydroxyflutamide.
Anandron, another
androgen receptor antagonist, was able to reverse all inhibitory and stimulatory actions of the
androgens. AR
antisense oligonucleotides reduced the level of immunoreactive AR expression in MDA-MB-453 and ZR-75-1 cells by more than 60%, but only reversed the growth inhibitory action of
mibolerone in ZR-75-1 cultures. The results suggest that
androgen action in
breast cancer cell lines may not be solely mediated by binding of
androgen to the AR. For example, metabolites of DHT with oestrogenic activity, or
androgen binding to receptors other than the AR, may explain the divergent responses to
androgens observed in different
breast cancer cell lines.