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Breast Cancer Research and Treatment

, Volume 81, Issue 1, pp 81–93 | Cite as

Oestrogen Receptor-Mediated Modulation of the EGFR/MAPK Pathway in Tamoxifen-Resistant MCF-7 Cells

  • Iain R. Hutcheson
  • Janice M. Knowlden
  • Tracie-Ann Madden
  • Denise Barrow
  • Julia M.W. Gee
  • Alan E. Wakeling
  • Robert I. Nicholson
Article

Abstract

Oestrogen receptor (ER) levels are usually maintained on acquisition of tamoxifen resistance in the clinic, however, tumour re-growth is associated with increased expression of epidermal growth factor receptor (EGFR) and activation of the mitogen activated protein kinase (MAPK) pathway. In the present study we have used the ER down-regulator fulvestrant ('Faslodex') to investigate the influence of the ER on growth of a tamoxifen-resistant (TAM-R) human breast cancer cell line. Expression levels of ER mRNA and protein were equivalent in parental wild-type MCF-7 (WT) and TAM-R cells. Fulvestrant eliminated ER protein expression and inhibited proliferation in both cell lines. The growth inhibitory effects of fulvestrant were associated with a decrease in basal EGFR, c-erbB2 and ERK1/2 activity in TAM-R but not WT cells. ER functionality as determined by oestrogen response element (ERE)-luciferase reporter activity and expression of PgR, pS2 and transforming growth factor alpha (TGFα) was significantly reduced in TAM-R compared to WT cells and was further decreased by fulvestrant treatment in both cell lines. Epidermal growth factor (EGF) and TGFα significantly increased EGFR/MAPK pathway activity in both cell lines. Ligand-induced EGFR/MAPK activation promoted TAM-R cell growth in both the absence and presence of fulvestrant, whereas no proliferative activity was observed under the same conditions in WT cells. These results suggest that the ER modulates EGFR/MAPK signalling efficiency in TAM-R cells possibly through the regulation of TGFα availability. This effect may be overcome by the action of exogenous EGFR ligands, which strengthen EGFR/MAPK signalling activity to generate endocrine-insensitive cell growth.

c-erbB2 epidermal growth factor receptor fulvestrant mitogen-activated protein kinase oestrogen receptor tamoxifen-resistance transforming growth factor alpha 

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Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Iain R. Hutcheson
    • 1
  • Janice M. Knowlden
    • 1
  • Tracie-Ann Madden
    • 1
  • Denise Barrow
    • 1
  • Julia M.W. Gee
    • 1
  • Alan E. Wakeling
    • 2
  • Robert I. Nicholson
    • 1
  1. 1.Tenovus Centre for Cancer Research, Welsh School of PharmacyCardiff UniversityCardiffUK
  2. 2.AstraZeneca PharmaceuticalsCheshireUK

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