17β-Estradiol enhances breast cancer cell motility and invasion via extra-nuclear activation of actin-binding protein ezrin

PLoS One. 2011;6(7):e22439. doi: 10.1371/journal.pone.0022439. Epub 2011 Jul 26.

Abstract

Estrogen promotes breast cancer metastasis. However, the detailed mechanism remains largely unknown. The actin binding protein ezrin is a key component in tumor metastasis and its over-expression is positively correlated to the poor outcome of breast cancer. In this study, we investigate the effects of 17β-estradiol (E2) on the activation of ezrin and its role in estrogen-dependent breast cancer cell movement. In T47-D breast cancer cells, E2 rapidly enhances ezrin phosphorylation at Thr(567) in a time- and concentration-dependent manner. The signalling cascade implicated in this action involves estrogen receptor (ER) interaction with the non-receptor tyrosine kinase c-Src, which activates the phosphatidylinositol-3 kinase/Akt pathway and the small GTPase RhoA/Rho-associated kinase (ROCK-2) complex. E2 enhances the horizontal cell migration and invasion of T47-D breast cancer cells in three-dimensional matrices, which is reversed by transfection of cells with specific ezrin siRNAs. In conclusion, E2 promotes breast cancer cell movement and invasion by the activation of ezrin. These results provide novel insights into the effects of estrogen on breast cancer progression and highlight potential targets to treat endocrine-sensitive breast cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / enzymology
  • Breast Neoplasms / pathology*
  • Cell Movement / drug effects*
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism*
  • Cytoskeletal Proteins / metabolism*
  • Cytoskeleton / drug effects
  • Cytoskeleton / metabolism
  • Enzyme Activation / drug effects
  • Estradiol / pharmacology*
  • Estrogen Receptor alpha / metabolism
  • Female
  • Humans
  • Intracellular Space / drug effects
  • Intracellular Space / metabolism
  • Microfilament Proteins / metabolism*
  • Neoplasm Invasiveness
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects
  • rho-Associated Kinases / metabolism
  • rhoA GTP-Binding Protein / metabolism
  • src-Family Kinases / metabolism

Substances

  • Cytoskeletal Proteins
  • Estrogen Receptor alpha
  • Microfilament Proteins
  • estrogen receptor alpha, human
  • ezrin
  • Estradiol
  • Phosphatidylinositol 3-Kinases
  • src-Family Kinases
  • Proto-Oncogene Proteins c-akt
  • ROCK2 protein, human
  • rho-Associated Kinases
  • rhoA GTP-Binding Protein