Oncogenic role of the ubiquitin ligase subunit Skp2 in human breast cancer

J Clin Invest. 2002 Sep;110(5):633-41. doi: 10.1172/JCI15795.


Estrogen receptor (ER) expression and Her-2 amplification define specific subsets of breast tumors for which specific therapies exist. The S-phase kinase-associated protein Skp2 is required for the ubiquitin-mediated degradation of the cdk-inhibitor p27 and is a bona fide proto-oncoprotein. Using microarray analysis and immunohistochemistry, we determined that higher levels of Skp2 are present more frequently in ER-negative tumors than in ER-positive cases. Interestingly, the subset of ER-negative breast carcinomas overexpressing Skp2 are also characterized by high tumor grade, negativity for Her-2, basal-like phenotype, high expression of certain cell cycle regulatory genes, and low levels of p27 protein. We also found that Skp2 expression is cell adhesion-dependent in normal human mammary epithelial cells but not in breast cancer cells and that an inhibition of Skp2 induces a decrease of adhesion-independent growth in both ER-positive and ER-negative cancer cells. Finally, forced expression of Skp2 abolished effects of antiestrogens, suggesting that deregulated Skp2 expression might play a role in the development of resistance to antiestrogens. We conclude that Skp2 has oncogenic potential in breast epithelial cells and is overexpressed in a subset of breast carcinomas (ER- and Her-2 negative) for which Skp2 inhibitors may represent a valid therapeutic option.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Retracted Publication

MeSH terms

  • Breast Neoplasms / enzymology*
  • Cell Adhesion
  • Cell Cycle
  • Cell Cycle Proteins / chemistry*
  • Cell Cycle Proteins / metabolism
  • Cell Cycle Proteins / physiology*
  • Cell Division
  • Cyclin-Dependent Kinase Inhibitor p27
  • Gene Transfer Techniques
  • Humans
  • Immunohistochemistry
  • Microscopy, Fluorescence
  • Oligonucleotide Array Sequence Analysis
  • Phenotype
  • Receptors, Estrogen
  • Retroviridae / genetics
  • S-Phase Kinase-Associated Proteins
  • Time Factors
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins / metabolism


  • Cell Cycle Proteins
  • Receptors, Estrogen
  • S-Phase Kinase-Associated Proteins
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27