Caveolin-1 Regulates EGFR Signaling in MCF-7 Breast Cancer Cells and Enhances Gefitinib-Induced Tumor Cell Inhibition

Cancer Biol Ther. 2009 Aug;8(15):1470-7. doi: 10.4161/cbt.8.15.8939. Epub 2009 Aug 8.

Abstract

Caveolin-1, an essential protein constituent of caveolae, is involved in cell signaling through its association with various signaling molecules. Epidermal growth factor receptor (EGFR) interacts directly with caveolin-1 and this interaction functionally regulates EGFR tyrosine kinase activity. In this report we investigated the role of caveolin-1 overexpression on EGFR signaling in MCF-7 breast cancer cell line. We demonstrate here that although total EGFR expression levels are similar, EGFR phosphorylation is diminished in MCF-7/CAV1 cells compared to parental MCF-7 cells. In addition, MCF-7/CAV1 cells exhibit higher total and activated Akt levels. Moreover, MCF-7/CAV1 cells stimulated with EGF display higher EGFR and Akt phosphorylation associated with enhanced proliferative and motility rates, compared to MCF-7 cells. Pretreatment with gefitinib inhibits EGF-induced stimulation of both EGFR and downstream Akt and MAPK more efficiently in MCF-7/CAV1 than in MCF-7 cells. In accordance, EGF-induced proliferation and migration is more effectively suppressed with gefinitib in MCF-7/CAV1 compared to parental cells. In conclusion these results suggest that caveolin-1 overexpression in MCF-7 breast cancer cell line modulates EGFR activation levels and EGF-induced EGFR signalling. This is associated with enhanced antitumor effects of gefitinib suggesting a role for EGFR inhibition in caveolin-1 overexpressing breast cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology*
  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Caveolin 1 / antagonists & inhibitors
  • Caveolin 1 / physiology*
  • Cell Division / drug effects
  • Cell Line, Tumor / metabolism
  • Cell Movement / drug effects
  • Enzyme Activation
  • Enzyme Induction / physiology
  • ErbB Receptors / biosynthesis
  • ErbB Receptors / physiology*
  • Female
  • Gefitinib
  • Genes, erbB-1
  • Humans
  • MAP Kinase Signaling System
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Processing, Post-Translational
  • Proto-Oncogene Proteins c-akt / biosynthesis
  • Proto-Oncogene Proteins c-akt / genetics
  • Quinazolines / pharmacology*
  • Signal Transduction / physiology*

Substances

  • Antineoplastic Agents
  • CAV1 protein, human
  • Caveolin 1
  • Neoplasm Proteins
  • Protein Kinase Inhibitors
  • Quinazolines
  • EGFR protein, human
  • ErbB Receptors
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt
  • Gefitinib