THE PRAD-1 CYCLIN D1 ONCOGENE PRODUCT ACCUMULATES ABERRANTLY IN A SUBSET OF COLORECTAL CARCINOMAS

The PRAD-1/cyclin D1 proto-oncogene is localized on chromosome 11q13 a nd it is overexpressed in several tumour types as a consequence of gen e amplification or chromosomal rearrangements. In this study, the abun dance and patterns of cyclin D1 protein expression in normal/non-invol ved colon (n = 44), primary (n = 48) and metastatic (n = 9) colorectal carcinomas, and in a series of 4 colon cancer cell lines were investi gated by immunochemical methods using the DCS-6 monoclonal antibody sp ecific for cyclin D1. While examination of all normal colorectal tissu e samples and 56% of the primary tumours revealed only weak to undetec table immunostaining signals, 23% of the primary carcinomas showed mod erate and 21% showed strong aberrant accumulation of this cell-cycle r egulatory oncoprotein. The immunohistochemical patterns in the seconda ry lesions were concordant with the matched primary tumours in all cas es. The staining was nuclear both in the clinical specimens and in the colon cancer cell lines, in which the antibody-mediated knock-out exp eriments demonstrated a positive regulatory role of the cyclin D1 prot ein whose function was required for progression through the G1 phase o f the cell cycle. These results indicate that the PRAD-1/cyclin D1 pro to-oncogene may be deregulated in a significant subset of colorectal t umours, and warrant further analyses of such aberrations of the cyclin D1/retinoblastoma protein pathway to elucidate its potential involvem ent in the multistep pathogenesis of human colorectal cancer. (C) 1994 Wiley-Liss, Inc.