Breast Cancer Research and Treatment

, Volume 115, Issue 2, pp 289–296

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

  • Matthew J. Sikora
  • Kevin E. Cordero
  • Jose M. Larios
  • Michael D. Johnson
  • Marc E. Lippman
  • James M. Rae
Preclinical Study

DOI: 10.1007/s10549-008-0080-8

Cite this article as:
Sikora, M.J., Cordero, K.E., Larios, J.M. et al. Breast Cancer Res Treat (2009) 115: 289. doi:10.1007/s10549-008-0080-8

Abstract

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 5α-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 5α-dihydrotestosterone, 5α-androstane-3β,17β-diol (3βAdiol), is estrogenic in breast cancer cells, and induces growth and ER-signaling via activation of ERα. 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.

Keywords

Breast cancer 3βAdiol Estrogen receptor 

Abbreviations

ER

Estrogen receptor

3βAdiol

5α-androstane-3β,17β-diol

AI

Aromatase inhibitor

E2

17β-estradiol

TS

Testosterone

DHT

5α-dihydrotestosterone

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Matthew J. Sikora
    • 1
  • Kevin E. Cordero
    • 2
  • Jose M. Larios
    • 2
  • Michael D. Johnson
    • 3
  • Marc E. Lippman
    • 2
  • James M. Rae
    • 1
    • 2
    • 4
  1. 1.Department of PharmacologyUniversity of Michigan Medical CenterAnn ArborUSA
  2. 2.Department of Internal MedicineUniversity of Michigan Medical CenterAnn ArborUSA
  3. 3.Lombardi Cancer Center and Department of OncologyGeorgetown University Medical CenterWashingtonUSA
  4. 4.Division of Hematology/Oncology, Department of Internal MedicineUniversity of Michigan Medical CenterAnn ArborUSA

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