Subcellular localisation of cyclin D1 protein in colorectal tumours is associated with p21(WAF1/CIP1) expression and correlates with patient survival

We investigated the expression of the cell cycle regulatory proteins cyclin D1 and p21(WAFI/CIPI) (p21) in human colorectal carcinomas using immunohis tochemistry. Cyclin D1 was not detected in normal colonic epithelium; howev er, expression was observed in 74/126 (58.7%) of the tumour samples studied . Protein was detected in the nucleus in 22/126 (17.4%) and exclusively in the cytoplasm in 52/126 (41.3%) tumours. Nuclear expression of cyclin D1 wa s associated with poorly differentiated tumours (p = 0.035) and was more co mmon in right- than in left-sided tumours (p = 0.005). Tumours displaying e ither, expression of cytoplasmic, (p = 0.05, HR 0.56, 95% CI 0.31-1.0) or n uclear (p = 0.021, HR 0.24, 95% CI 0.07-0.81) cyclin D1 were associated wit h improved patient survival compared with tumours negative for cyclin D1. p 21 protein was strongly expressed mainly in the upper crypts of normal colo nic epithelial cells, but in 63/126 (50%) of the tumour samples studied p21 expression was absent. Patients with tumours in which > 50% of cells expre ssed p21 had improved survival compared to patients whose tumours were nega tive or had :less than or equal to 50% of cells expressing p21 (p = 0.06, H R 0.33, 95% CI 0.1-1.0). We also observed a significant association between cyclin DI subcellular localisation and p21 expression: 21/22 (95.5%) tumou rs expressing cyclin D1 in the nucleus also expressed p21, whereas only 17/ 52 (32.7%) of the tumours displaying exclusive cytoplasmic cyclin D1 staini ng were positive for p21 (p < 0.001). These data highlight the significance of exclusive cytoplasmic expression of cyclin D1 in colorectal cancer and lend support to recent in vitro studies suggesting that p21 protein may mod ulate the subcellular localisation of the cyclin D1 protein. Thus, deregula ted expression of the cyclin D1 and p21 proteins are important in colorecta l tumourigenesis and have implications for patient prognosis. (C) 2001 Wile y-Liss, Inc.