Oncogenic role of the ubiquitin ligase subunit Skp2 in human breast cancer.
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.
Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Sabina
S
Signoretti
Lucia
L
Di Marcotullio
Andrea
A
Richardson
Sridhar
S
Ramaswamy
Beth
B
Isaac
Montserrat
M
Rue
Franco
F
Monti
Massimo
M
Loda
Michele
M
Pagano
D001943:Breast Neoplasms / Q000201:enzymology*; D002448:Cell Adhesion; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D002455:Cell Division; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018014:Gene Transfer Techniques; D006801:Humans; D007150:Immunohistochemistry; D008856:Microscopy, Fluorescence; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011960:Receptors, Estrogen; D012190:Retroviridae / Q000235:genetics; D044786:S-Phase Kinase-Associated Proteins; D013997:Time Factors; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D018797:Cell Cycle Proteins; D011960:Receptors, Estrogen; D044786:S-Phase Kinase-Associated Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27