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

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2002
Author
Signoretti, Sabina
Di Marcotullio, Lucia
Richardson, Andrea
Ramaswamy, Sridhar
Isaac, Beth
Rué i Monné, Montserrat
Monti, Franco
Loda, Massimo
Pagano, Michele
Suggested citation
Signoretti, Sabina; Di Marcotullio, Lucia; Richardson, Andrea; Ramaswamy, Sridhar; Isaac, Beth; Rué i Monné, Montserrat; ... Pagano, Michele. (2002) . Oncogenic role of the ubiquitin ligase subunit Skp2 in human breast cancer. Journal of Clinical Investigation, 2002, vol.110, núm. 5, p. 633-641. https://doi.org/10.1172/JCI15795.
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Abstract
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.
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http://hdl.handle.net/10459.1/56695
DOI
https://doi.org/10.1172/JCI15795
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Journal of Clinical Investigation, 2002, vol.110, núm. 5, p. 633-641
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