Inhibition of HER2/neu (erbB-2) and mitogen-activated protein kinases enhances tamoxifen action against HER2-overexpressing, tamoxifen-resistant breast cancer cells

Cancer Res. 2000 Oct 15;60(20):5887-94.

Abstract

HER2/neu (erbB-2) overexpression has been causally associated with tamoxifen resistance in human breast cancer cells. Forced expression of HER2 in MCF-7 breast cancer cells resulted in mitogen-activated protein kinase (MAPK) hyperactivity and tamoxifen resistance. Inhibition of HER2 and MAPKs with AG1478 and U0126, respectively, as well as dominant-negative MEK-1/2 constructs restored the inhibitory effect of tamoxifen on estrogen receptor (ER)-mediated transcription and cell proliferation. Both AG1478 and U0126 also restored the tamoxifen-mediated association of ER with nuclear receptor corepressor (N-CoR) in the antiestrogen-resistant MCF-7 cells. Treatment with a combination of tamoxifen and a HER2 kinase inhibitor reduced tumor MAPK activity and markedly prevented growth of HER2-overexpressing MCF-7 xenografts in athymic mice. Thus, blockade of HER2 and MAPK signaling may enhance tamoxifen action and abrogate antiestrogen resistance in human breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / genetics
  • Butadienes / pharmacology
  • Drug Resistance, Neoplasm
  • Enzyme Inhibitors / pharmacology
  • Estrogen Receptor Modulators / pharmacology*
  • Female
  • Gene Expression
  • Humans
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Mice
  • Mice, Nude
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Nitriles / pharmacology
  • Quinazolines
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Receptor, ErbB-2 / biosynthesis
  • Receptor, ErbB-2 / genetics
  • Receptors, Estrogen / physiology
  • Tamoxifen / pharmacology*
  • Transcription, Genetic / drug effects
  • Tyrphostins / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • Butadienes
  • Enzyme Inhibitors
  • Estrogen Receptor Modulators
  • Nitriles
  • Quinazolines
  • Receptors, Estrogen
  • Tyrphostins
  • U 0126
  • Tamoxifen
  • RTKI cpd
  • Receptor, ErbB-2
  • Mitogen-Activated Protein Kinases