Nature Medicine
3, 231 - 234 (1997)
doi:10.1038/nm0297-231
Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomasMassimo Loda1, Barry Cukor1, Sun W. Tam2, Philip Lavin3, Michelangelo Fiorentinc1, Glulio F. Draetta4, J. Milburn Jessup5
& Michele Pagano2, 6, 7
1Department of Pathology, Beth Israel Deaconess Medical Center, West Campus, Harvard Medical School, 1 Deaconess Road, Boston, Massachusetts 02215, USA
2Mitotix Inc., One Kendall Square, Building 600, Cambridge, Massachusetts 02139, USA (paganm02@mcrcr.med.nyu.edu)
3Boston Biostatistics Research Foundation, Inc., 615 Concord Street, Framingham, Massachusetts 01702, USA
4European Institute of Oncology, Via Ripamonti, 435, Milan, 20141, Italy
5Department of Surgery, Beth Israel Deaconess Medical Center, West Campus, Harvard Medical School, 1 Deaconess Road, Boston, Massachusetts 02215, USA
6Department of Pathology, MSB 548, New York University Medical Center, 550 First Avenue, New York, New York 10016, USA
7paganm02@mcrcr.med.nyu.edu The cell-cycle inhibitor p27 is a potential tumor suppressor, but its gene has never been found inactivated in human tumors1−4. Because cell-cycle regulation of p27 cellular abundance occurs at the post-transcriptional level5−7, we analyzed p27 protein expression and degradation in human colorectal carcinomas. Proteasome-mediated degradation activity of p27 was compared with its protein levels in a subset of tumor samples. We found that carcinomas with low or absent p27 protein displayed enhanced proteolytic activity specific for p27, suggesting that low p27 expression can result from increased proteasome-mediated degradation rather than altered gene expression. Patients whose tumors expressed p27 had a median survival of 151 months, whereas patients who lacked p27 (10%) had a median survival of 69 months. By multivariate analysis, p27 was found to be an independent prognostic marker. Lack of p27 was associated with poor prognosis (2.9 risk ratio for death; P = 0.003). The absence of p27 protein expression is thus a powerful negative prognostic marker in colorectal carcinomas, particularly in stage II tumors, and thereby may help in the selection of patients who will benefit from adjuvant therapy. These data suggest that aggressive tumors may result from the selection of a clone or clones that lack p27 due to increased proteasome-mediated degradation.
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