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

Sabina Signoretti, Lucia Di Marcotullio, Andrea Richardson, Sridhar Ramaswamy, Beth Isaac, Montserrat Rue, Franco Monti, Massimo Loda, Michele Pagano

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)633-641
Number of pages9
JournalJournal of Clinical Investigation
Volume110
Issue number5
DOIs
StatePublished - Sep 2002
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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