Estradiol stabilizes the 105-kDa phospho-form of the adhesion docking protein NEDD9 and suppresses NEDD9-dependent cell spreading in breast cancer cells

Biochim Biophys Acta. 2011 Feb;1813(2):340-5. doi: 10.1016/j.bbamcr.2010.11.018. Epub 2010 Dec 8.


Recent data suggest that the adhesion docking protein NEDD9/HEF1/Cas-L is a critical regulator of adhesion-dependent signalling pathways during mammary tumour development. Multiple phosphorylation modifications of NEDD9 regulate interaction with downstream protein partners, thus the regulation of NEDD9 phospho-forms is an important point of control for NEDD9 function. As estradiol (E2) plays a central role in the development and progression of breast cancer, we have investigated NEDD9 phospho-form regulation in MCF-7 estrogen receptor (ER)-positive breast cancer cells in response to estrogen. We find that levels of the 105-kDa NEDD9 phospho-form are significantly increased after 3days of estrogen exposure, and this is suppressed by the anti-estrogen tamoxifen. Analysis of protein decay kinetics following treatment with the protein synthesis inhibitor cycloheximide indicates that increased 105-kDa levels are due to a slower rate of protein decay. Moreover, exogenous expression of NEDD9 failed to induce spreading in the presence of E2, and this was reversed by tamoxifen treatment. Finally, we show that the 105-kDa NEDD9 phospho-form appears to predominate in ER-positive versus ER-negative breast cancer cell lines. Taken together, our results suggest that estradiol may suppress phospho-form-specific functions of NEDD9.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Antineoplastic Agents, Hormonal / pharmacology
  • Blotting, Western
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Cell Adhesion / drug effects
  • Cell Movement / drug effects*
  • Cell Proliferation / drug effects
  • Estradiol / pharmacology*
  • Female
  • Humans
  • Phosphoproteins / metabolism*
  • Phosphorylation / drug effects
  • Receptors, Estrogen / metabolism
  • Signal Transduction / drug effects
  • Tamoxifen / pharmacology
  • Tumor Cells, Cultured


  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents, Hormonal
  • NEDD9 protein, human
  • Phosphoproteins
  • Receptors, Estrogen
  • Tamoxifen
  • Estradiol