Title | Oncogenic role of the ubiquitin ligase subunit Skp2 in human breast cancer. |
Publication Type | Journal Article |
Year of Publication | 2002 |
Authors | Signoretti S, Di Marcotullio L, Richardson A, Ramaswamy S, Isaac B, Rue M, Monti F, Loda M, Pagano M |
Journal | J Clin Invest |
Volume | 110 |
Issue | 5 |
Pagination | 633-41 |
Date Published | 2002 Sep |
ISSN | 0021-9738 |
Keywords | Breast Neoplasms, Cell Adhesion, Cell Cycle, Cell Cycle Proteins, Cell Division, Cyclin-Dependent Kinase Inhibitor p27, Gene Transfer Techniques, Humans, Immunohistochemistry, Microscopy, Fluorescence, Oligonucleotide Array Sequence Analysis, Phenotype, Receptors, Estrogen, Retroviridae, S-Phase Kinase-Associated Proteins, Time Factors, Tumor Cells, Cultured, Tumor Suppressor Proteins |
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. |
DOI | 10.1172/JCI15795 |
Alternate Journal | J Clin Invest |
PubMed ID | 12208864 |
PubMed Central ID | PMC151109 |
Grant List | U01 CA084995 / CA / NCI NIH HHS / United States R01-CA81755 / CA / NCI NIH HHS / United States R01-GM57587 / GM / NIGMS NIH HHS / United States R01 GM057587 / GM / NIGMS NIH HHS / United States P50 CA089393 / CA / NCI NIH HHS / United States R01-CA76584 / CA / NCI NIH HHS / United States CA84995 / CA / NCI NIH HHS / United States R01 CA076584 / CA / NCI NIH HHS / United States CA89393 / CA / NCI NIH HHS / United States |
Related Faculty:
Massimo Loda, M.D.