The androgen metabolite 5alpha-androstane-3beta,17beta-diol (3betaAdiol) induces breast cancer growth via estrogen receptor: implications for aromatase inhibitor resistance

Breast Cancer Res Treat. 2009 May;115(2):289-96. doi: 10.1007/s10549-008-0080-8. Epub 2008 Jun 4.


The aromatase inhibitors (AIs) are used to treat estrogen receptor-positive (ER+) breast tumors in post-menopausal women, and function by blocking the conversion of adrenal androgens to estrogens by the enzyme CYP19 aromatase. Breast cancer patients receiving AI therapy have circulating estrogen levels below the level of detection; however, androgen concentrations remain unchanged. We were interested in studying the effects of androgens on breast cancer cell proliferation under profound estrogen-deprived conditions. Using in vitro models of estrogen-dependent breast cancer cell growth we show that the androgens testosterone and 5alpha-dihydrotestosterone induce the growth of MCF-7, T47D and BT-474 cells in the absence of estrogen. Furthermore, we demonstrate that under profound estrogen-deprived conditions these breast cancer cells up-regulate steroidogenic enzymes that can metabolize androgens to estrogens. Lastly, we found that the downstream metabolite of 5alpha-dihydrotestosterone, 5alpha-androstane-3beta,17beta-diol (3betaAdiol), is estrogenic in breast cancer cells, and induces growth and ER-signaling via activation of ERalpha. In conclusion, our results show that breast cancer cells deprived of estrogen up-regulate steroidogenic enzymes and metabolize androgens to estrogen-like steroids. The generation of estrogen-like steroids represents a potential mechanism of resistance to aromatase inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgens / metabolism
  • Androgens / pharmacology
  • Androstane-3,17-diol / metabolism*
  • Aromatase Inhibitors / therapeutic use*
  • Blotting, Western
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation* / drug effects
  • Drug Resistance, Neoplasm / physiology*
  • Estrogen Receptor Modulators / pharmacology
  • Estrogen Receptor alpha / drug effects
  • Estrogen Receptor alpha / metabolism*
  • Female
  • Humans
  • Reverse Transcriptase Polymerase Chain Reaction


  • Androgens
  • Aromatase Inhibitors
  • Estrogen Receptor Modulators
  • Estrogen Receptor alpha
  • Androstane-3,17-diol