Characterization of the weak estrogen receptor alpha agonistic activity of exemestane

Breast Cancer Res Treat. 2009 Aug;116(3):461-70. doi: 10.1007/s10549-008-0151-x. Epub 2008 Aug 3.


Third generation aromatase inhibitors (AI) have shown good clinical efficacy in comparison to the anti-estrogen tamoxifen. The steroidal AI, exemestane (EXE) has previously been shown to act as an androgen, but this report demonstrates the estrogen-like activity of EXE. Based on genome-wide microarray analysis, high correlation was seen between EXE-Only (EXE O, hormone-free) and hormone-containing AI-resistant lines. In addition, the top regulated genes in the EXE O lines were mostly estrogen-responsive genes. This estrogen-like activity of EXE was further validated using estrogen receptor (ER) activity assays, where in comparison to 17beta-estradiol (E2), EXE was able to induce ER activity, though at a higher concentration. Also, this EXE-mediated ER activity was blocked by the ER antagonist ICI as well as the ERalpha-specific antagonist methyl-piperidino-pyrazole (MPP). Similarly, EXE was able to induce proliferation of breast cancer cell lines, MCF-7 and MCF-7aro, as well as activate transcription of known estrogen-responsive genes, i.e., PGR, pS2 and AREG. These results suggest that EXE does have weak estrogen-like activity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anastrozole
  • Androstadienes / pharmacology*
  • Aromatase Inhibitors / pharmacology
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Proliferation
  • Drug Resistance, Neoplasm*
  • Estrogen Receptor alpha / agonists*
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Female
  • Gene Expression Profiling
  • Humans
  • Microarray Analysis
  • Nitriles / pharmacology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Triazoles / pharmacology
  • Tumor Cells, Cultured


  • Androstadienes
  • Aromatase Inhibitors
  • Estrogen Receptor alpha
  • Nitriles
  • RNA, Messenger
  • Triazoles
  • Anastrozole
  • exemestane

Associated data

  • GEO/GSE10911