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

Authors: Hutcheson I.R.¹; Knowlden J.M.¹; Madden T-A.¹; Barrow D.¹; Gee J.M.W.¹; Wakeling A.E.²; Nicholson R.I.¹

Source: Breast Cancer Research and Treatment, Volume 81, Number 1, September 2003 , pp. 81-93(13)

Publisher: Springer

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 (TGF) 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 TGF 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 TGF 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.

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

Language: English

Document Type: Research article

Affiliations: 1: Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff University, Cardiff, UK 2: AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire, UK

Publication date: 2003-09-01

• In this: publication
• By this: publisher
• In this Subject: Obstetrics & Gynecology ,  Oncology
• By this author: Hutcheson I.R. ;  Knowlden J.M. ;  Madden T-A. ;  Barrow D. ;  Gee J.M.W. ;  Wakeling A.E. ;  Nicholson R.I.

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