Increased expression of Nrf2/ARE-dependent anti-oxidant proteins in tamoxifen-resistant breast cancer cells

Free Radic Biol Med. 2008 Aug 15;45(4):537-46. doi: 10.1016/j.freeradbiomed.2008.05.011. Epub 2008 May 24.


Acquired resistance to tamoxifen (TAM) is a serious therapeutic problem in breast cancer patients. In this study, we found that the expressions of anti-oxidant proteins (gamma-glutamylcysteine ligase heavy chain (gamma-GCL h), heme oxygenase-1, thioredoxin and peroxiredoxin1) in TAM-resistant MCF-7 (TAMR-MCF-7) cells were higher than control MCF-7 cells. Molecular analyses using antioxidant response element (ARE)-containing reporters and gel-shift supported the critical role of NF-E2-related factor2 (Nrf2)/ARE in the overexpression of antioxidant proteins in TAMR-MCF-7 cells. Intracellular peroxide production was significantly decreased in TAMR-MCF-7 cells and TAM resistance was partially reversed by Nrf2 siRNA. The basal phosphorylation of extracellular signal-regulated kinase (ERK) and p38 kinase were increased in the TAMR-MCF-7 cells and the inhibition of ERK significantly decreased the activity of minimal ARE reporter and gamma-GCL h protein expression in TAMR-MCF-7 cells. However, exposure of TAMR-MCF-7 cells to 17-beta-estradiol or ICI-182,780 did not significantly change gamma-GCL h expression. These results suggest that the persistent activation of Nrf2/ARE is critical for the enhanced expression of anti-oxidant proteins in TAM-resistant breast cancer cells and the pathway of ERK, but not of estrogen receptor signaling are involved in the up-regulation of Nrf2/ARE.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Hormonal / pharmacology*
  • Antioxidants / metabolism*
  • Base Sequence
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm*
  • Glutamate-Cysteine Ligase / metabolism
  • Humans
  • NF-E2-Related Factor 2 / metabolism*
  • NF-kappa B / metabolism
  • RNA, Small Interfering
  • Receptors, Estrogen / metabolism
  • Signal Transduction
  • Tamoxifen / pharmacology*


  • Antineoplastic Agents, Hormonal
  • Antioxidants
  • NF-E2-Related Factor 2
  • NF-kappa B
  • NFE2L2 protein, human
  • RNA, Small Interfering
  • Receptors, Estrogen
  • Tamoxifen
  • Glutamate-Cysteine Ligase