Androgens Inhibit the Stimulatory Action of 17β-Estradiol on Normal Human Breast Tissue in Explant Cultures

Background: The data concerning the effects and safety of androgen in human breast tissue are conflicting. Objective: Our aim was to analyze the effects of androgens on normal human breast tissue (HBT). Approach: We cultured explants of HBT (obtained from reduction mammoplasty operations of postmenopausal women) with or without testosterone (T) and 5 alpha-dihydrotestosterone (DHT) or in combination with 17 beta-estradiol (E-2) for 7 and 14 d to study the effects of androgens on proliferation, apoptosis, target gene expression, and steroid receptors. The androgen receptor (AR) and estrogen receptor (ER) dependences of the effects were studied with the antihormones bicalutamide and fulvestrant, respectively. Results: The hormone responsiveness of cultured breast tissue was assessed by assaying apolipoprotein-D and prostate-specific antigen expression increased by androgens and amphiregulin and trefoil factor-1 expression induced by E-2 treatment. T and DHT reduced proliferation and increased apoptosis in breast epithelium, the effects of which were reversed by bicalutamide. In combination with E-2, they suppressed E-2-stimulated proliferation and cell survival. DHT also inhibited basal (P < 0.05) and E-2-induced expression of cyclin-D1 mRNA(P < 0.05). Immunohistochemistry showed that T (P < 0.05) and DHT (P < 0.05) increased the relative number of AR-positive cells, whereas ER alpha-positive (P < 0.001) cell numbers were strongly decreased. The percentage of ER beta-positive cells remained unchanged. E-2 treatment-increased ER alpha-positive (P < 0.01) cells, whereas AR-(P < 0.05) and ER beta-expressing (P < 0.001) cells diminished. These effects were repressed in combination cultures of E-2 with T and DHT. Conclusion: T and DHT inhibited proliferation and increased apoptosis in the epithelium of cultured normal HBT and opposed E-2-stimulated proliferation and cell survival in an AR-dependent manner. These effects were associated with changes in the proportions of ER alpha- and AR-positive epithelial cells. (J Clin Endocrinol Metab 97: E1116-E1127, 2012)