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Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
10:36

Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer

Published on: March 17, 2016

Interactions between MAP kinase and oestrogen receptor in human breast cancer

Liane M McGlynn1, Sian Tovey, John M S Bartlett

  • 1Institute of Cancer Sciences, College of MVLS, University of Glasgow, Western Infirmary, Glasgow G11 6NT, UK. liane.mcglynn@glasgow.ac.uk

European Journal of Cancer (Oxford, England : 1990)
|December 26, 2012
PubMed
Abstract

Insights

Mitogen Activated Protein Kinase (MAPK) phosphorylates oestrogen receptor alpha (ERα) ligand-independently. This interaction influences ERα localization in breast cancer cells, with heregulin signaling playing a key role in ERα subcellular distribution.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Endocrinology

Background:

  • Oestrogen receptor alpha (ERα) can be activated by oestrogen (ligand-dependent) or by signaling pathways (ligand-independent).
  • Mitogen Activated Protein Kinase (MAPK) is known to phosphorylate ERα at serine 118 in a ligand-independent manner.
  • Understanding the interplay between MAPK and ERα is crucial for breast cancer research.

Purpose of the Study:

  • To investigate the interaction between MAPK and ERα in breast cancer.
  • To determine the clinical relevance of MAPK, pMAPK, and pER(ser118) expression in breast tumors.
  • To elucidate the role of MAPK in the ligand-independent phosphorylation and localization of ERα.

Main Methods:

  • Immunohistochemistry to assess MAPK, pMAPK, and pER(ser118) expression in breast tumors.
  • Immunofluorescence in MCF-7 cells to observe MAPK and ERα phosphorylation and localization.
  • Treatment with oestrogen, heregulin, and a MAPK inhibitor to study signaling pathways.

Main Results:

  • Both oestrogen and heregulin stimulated ERα phosphorylation and nuclear translocation, with oestrogen showing a stronger effect.
  • Heregulin-induced ERα phosphorylation was reduced by a MAPK inhibitor, indicating a ligand-independent pathway.
  • MAPK inhibition affected ligand-independent ERα phosphorylation but not ligand-dependent phosphorylation.
  • Heregulin signaling appeared to dictate ERα subcellular localization, even under co-stimulation with oestrogen.

Conclusions:

  • Ligand-mediated ERα phosphorylation by oestrogen leads to rapid nuclear localization.
  • ERα phosphorylation at serine 118 occurs independently of ligand binding.
  • MAPK signaling is critical for ligand-independent ERα phosphorylation and influences its subcellular localization.
  • ERα activation via direct phosphorylation may be followed by rapid deactivation through degradation or nuclear export.

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