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Title:
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Oncogenic role of the ubiquitin ligase subunit Skp2 in human breast cancer
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Author:
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Signoretti, Sabina; Di Marcotullio, Lucia; Richardson, Andrea; Ramaswamy, Sridhar; Isaac, Beth; Rué i Monné, Montserrat; Monti, Franco; Loda, Massimo; Pagano, Michele
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Notes:
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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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Rights:
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(c) American Society for Clinical Investigation, 2002
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Document type:
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article
publishedVersion |
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Published by:
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American Society for Clinical Investigation
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