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

D J Britton1, I R Hutcheson, J M Knowlden

  • 1Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff University, Cardiff, UK.

Breast Cancer Research and Treatment
|November 2, 2005
PubMed

Insights

In tamoxifen-resistant breast cancer cells, epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK) signaling maintains oestrogen receptor alpha (ERalpha) function. This creates a self-sustaining loop promoting tumor growth via amphiregulin production.

Area of Science:

  • * Molecular Endocrinology
  • * Cancer Biology
  • * Signal Transduction

Background:

  • * Oestrogen receptor alpha (ERalpha) plays a crucial role in breast cancer, and its signaling can be altered in tamoxifen-resistant (Tam-R) cells.
  • * Epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK) signaling is frequently dysregulated in cancer and can interact with ERalpha pathways.

Purpose of the Study:

  • * To investigate the bidirectional cross-talk between EGFR/MAPK and ERalpha signaling pathways in tamoxifen-resistant MCF-7 breast cancer cells (Tam-R).
  • * To determine how EGFR/MAPK activity influences ERalpha functionality and contributes to Tam-R cell growth.

Main Methods:

  • * Comparison of ERalpha phosphorylation status between Tam-R and wild-type MCF-7 cells (WT-MCF-7).
  • * Assessment of EGFR/MAPK pathway regulation of ERalpha phosphorylation at serine 118 (S118) using specific inhibitors (gefitinib, PD184352) and ligands (amphiregulin, AR).
  • * Analysis of co-activator recruitment, oestrogen response element (ERE) activity, cell growth, and AR mRNA expression using chromatin immunoprecipitation (ChIP) and neutralizing antibodies.

Main Results:

  • * Elevated basal phosphorylation of ERalpha at S118 was observed in Tam-R cells compared to WT-MCF-7 cells.
  • * EGFR/MAPK pathway activity positively regulated ERalpha S118 phosphorylation, co-activator recruitment, ERE activity, and Tam-R cell growth.
  • * ERalpha assembled on the AR gene promoter in Tam-R cells, driving AR mRNA expression, which in turn was regulated by both EGFR/MAPK and ERalpha signaling.

Conclusions:

  • * EGFR/MAPK signaling maintains ERalpha functionality in Tam-R cells through phosphorylation at S118.
  • * This interaction establishes an autocrine growth-regulatory loop involving ERalpha-mediated production of amphiregulin (AR).
  • * Targeting the EGFR/MAPK pathway could be a therapeutic strategy for tamoxifen-resistant breast cancer by disrupting this self-sustaining growth loop.

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