Estrogen signals via an extra-nuclear pathway involving IGF-1R and EGFR in tamoxifen-sensitive and -resistant breast cancer cells

Steroids. 2009 Jul;74(7):586-94. doi: 10.1016/j.steroids.2008.11.020. Epub 2008 Dec 7.


Activation of IGF-1R can activate metalloproteinases which release heparin-binding EGF (Hb-EGF) and lead to EGFR-dependent MAPK activation in certain tissues. We postulated that this pathway is operative in E(2)-induced MAPK activation in breast cancer tissues. As evidence, we showed that E(2) rapidly induced the phosphorylation of both IGF-1R and EGFR and that siRNA knockdown or selective inhibitors against either growth factor receptor inhibited E(2)-induced MAPK activation. The selective inhibitors or knockdown of either IGF-1R or EGFR significantly inhibited cell growth and reversed cell death protection induced by E(2) in MCF-7 cells. Our data support the conclusion that the IGF-1R acts upstream of EGFR in a linear pathway which mediates E(2) action on MAPK activation, cell growth stimulation and anti-apoptosis in breast cancer cells. During the process of development of tamoxifen resistance this pathway is up-regulated with increased sensitivity to activate EGFR for cell growth and protection against apoptosis. Surprisingly, translocation of ERalpha out of the nucleus into the cytoplasm, mediated by c-Src, occurs during development of resistance. This effect can be abrogated by administration of the c-Src inhibitor, PP2 which also restores sensitivity to tamoxifen.

Publication types

  • Review

MeSH terms

  • Antineoplastic Agents, Hormonal / pharmacology*
  • Apoptosis
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Nucleus / metabolism*
  • Drug Resistance, Neoplasm*
  • ErbB Receptors / metabolism*
  • Estrogen Receptor alpha / metabolism
  • Estrogens / metabolism*
  • Humans
  • Receptor, IGF Type 1 / metabolism*
  • Signal Transduction
  • Tamoxifen / pharmacology*


  • Antineoplastic Agents, Hormonal
  • Estrogen Receptor alpha
  • Estrogens
  • Tamoxifen
  • ErbB Receptors
  • Receptor, IGF Type 1