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

• Published in: The Journal of clinical investigation 2002-09, Vol.110 (5), p.633-641
• Main Authors: Signoretti, Sabina, Di Marcotullio, Lucia, Richardson, Andrea, Ramaswamy, Sridhar, Isaac, Beth, Rue, Montserrat, Monti, Franco, Loda, Massimo, Pagano, Michele
• Format: Article
• Language: English
• Subjects: Biomedical research; Breast cancer; 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
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci0215795

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.