title: Androgens inhibit the stimulatory action of 17β-estradiol on normal human breast tissue in explant cultures.
abstract: 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).
  
  
  METHODS
  We cultured explants of HBT (obtained from reduction mammoplasty operations of postmenopausal women) with or without testosterone (T) and 5α-dihydrotestosterone (DHT) or in combination with 17β-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 ERα-positive (P < 0.001) cell numbers were strongly decreased. The percentage of ERβ-positive cells remained unchanged. E(2) treatment increased ERα-positive (P < 0.01) cells, whereas AR- (P < 0.05) and ERβ-expressing (P < 0.001) cells diminished. These effects were repressed in combination cultures of E(2) with T and DHT.
  
  
  CONCLUSIONS
  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 ERα- and AR-positive epithelial cells.
authors.affiliation: Department of Cell Biology and Anatomy, Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland.
authors.forename: Natalija
authors.initials: N
authors.lastname: Eigeliene
authors.forename: Teresa
authors.initials: T
authors.lastname: Elo
authors.forename: Mari
authors.initials: M
authors.lastname: Linhala
authors.forename: Saija
authors.initials: S
authors.lastname: Hurme
authors.forename: Risto
authors.initials: R
authors.lastname: Erkkola
authors.forename: Pirkko
authors.initials: P
authors.lastname: Härkönen
mesh_terms: D000728:Androgens / Q000494:pharmacology*; D001940:Breast / Q000166:cytology / Q000187:drug effects*; D002478:Cells, Cultured; D013196:Dihydrotestosterone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016462:Mammaplasty; D008875:Middle Aged; D009924:Organ Culture Techniques / Q000379:methods; D061251:Primary Cell Culture; D013739:Testosterone / Q000494:pharmacology
chemical_list: D000728:Androgens; D004338:Drug Combinations; D013196:Dihydrotestosterone; D013739:Testosterone; D004958:Estradiol