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

Hirokazu Kurokawa, Anne E.G. Lenferink, Jean F. Simpson, Paul I. Pisacane, Mark X. Sliwkowski, James T. Forbes, Carlos L. Arteaga

Research output: Contribution to journalArticlepeer-review

323 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5887-5894
Number of pages8
JournalCancer research
Volume60
Issue number20
StatePublished - Oct 15 2000

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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