Background:
The stabilization and nuclear translocation of beta-catenin are early events in the majority of sporadic colorectal carcinomas (crc). beta-catenin up-regulates c-myc and cyclin d1, which antagonize the association of the cyclin-dependent kinase (cdk) inhibitor, p27(kip1), with cdk2, thus allowing cell cycle progression through g1 to s-phase. lack of p27 is a significant predictor of poor survival in a series of 136 crc specimens. a combination of molecules in the same pathway may be a better prognostic factor.
Methods:
The expression of beta-catenin, c-myc, and cyclin d1 in relation to patients' survival and clinicopathologic parameters in the same series was evaluated by immunohistochemistry.
Results:
Intense nuclear overexpression of beta-catenin, but not a lack of cell membrane or cytoplasmic expression, is a significant predictor of poor survival by both univariate (p = 0.0029) and multivariate analyses (p = 0.004, risk ratio =3.8), suggesting that beta-catenin is retained in the nucleus to function as an oncogene. none of the patients with high nuclear beta-catenin and low p27 expression survived 5 years or more whereas 65% of patients with all other combinations of the two markers survived (p < 0.0001). this combination is also a significant and independent prognostic factor (p = 0.001; risk ratio = 9.7). overexpression of c-myc is associated with higher mortality rates, but the expression of cyclin d1 has no prognostic significance.
Conclusions:
The combined expression of beta-catenin and p27 can stratify patients into markedly different survival groups, possibly via their antagonistic effects on metastasis promotion.