Breast Cancer Research and Treatment

, Volume 96, Issue 2, pp 131–146

Bidirectional cross talk between ERα and EGFR signalling pathways regulates tamoxifen-resistant growth

  • D.J. Britton
  • I.R. Hutcheson
  • J.M. Knowlden
  • D. Barrow
  • M. Giles
  • R.A. McClelland
  • J.M.W. Gee
  • R.I. Nicholson
Preclinical study

Summary

We have previously demonstrated that oestrogen receptor α (ERα) modulates epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK) signalling efficiency in a tamoxifen-resistant MCF-7 breast cancer cell line (Tam-R). In the present study we have investigated whether this cross-talk between EGFR/MAPK and ERα signalling pathways is bidirectional by examining the effects of EGFR/MAPK activity on ER functionality in the same cell line. Elevated expression levels of phosphorylated serine 118 (S118) ERα were observed in the Tam-R compared to the parental wild type MCF-7 cell line (WT-MCF-7) under basal growth conditions. Phosphorylation of ERα at S118 was regulated by the EGFR/MAPK pathway in Tam-R cells being increased in response to amphiregulin (AR) and inhibited by the selective EGFR tyrosine kinase inhibitor, gefitinib and the MEK1/2 inhibitor, PD184352. Recruitment of the co-activators p68 RNA helicase and SRC1 to ERα, oestrogen response element (ERE) activity and Tam-R cell growth were similarly EGFR/MAPK-regulated. Chromatin immunoprecipitation (ChIP) studies revealed that in Tam-R cells the ERα assembled on the AR gene promoter and this was associated with elevated basal expression of AR mRNA. Furthermore, AR mRNA expression was under the regulation of the EGFR/MAPK and ERα signalling pathways. Neutralising antibodies to AR inhibited EGFR/ERK1/2 activity, reduced S118 ERα phosphorylation and reduced AR mRNA expression in TAM-R cells. These findings suggest that ERα function in Tam-R cells is maintained as a consequence of EGFR/MAPK-mediated phosphorylation at serine residue 118 resulting in the generation of a self-propogating autocrine growth-regulatory loop through the ERα-mediated production of AR.

Keywords

amphiregulin epidermal growth factor receptor oestrogen receptor α mitogen-activated protein kinase MCF-7 cells serine 118 tamoxifen resistance 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Copyright information

© Springer 2005

Authors and Affiliations

  • D.J. Britton
    • 1
  • I.R. Hutcheson
    • 2
  • J.M. Knowlden
    • 1
  • D. Barrow
    • 1
  • M. Giles
    • 1
  • R.A. McClelland
    • 1
  • J.M.W. Gee
    • 1
  • R.I. Nicholson
    • 1
  1. 1.Tenovus Centre for Cancer Research, Welsh School of PharmacyCardiff UniversityCardiffUK
  2. 2.Tenovus Centre for Cancer Research, Welsh School of PharmacyCardiff UniversityCardiffUK

Personalised recommendations