Expression of cell-cycle regulatory proteins in endometrial carcinomas: correlations with hormone receptor status and clinicopathologic parameters

Purpose: The normal human endometrium is characterized by hormone-dependent variations in the levels of cell-cycle regulatory proteins during the mens trual cycle. As this tightly controlled system is disturbed in endometrial carcinomas, we analyzed which cell-cycle regulators are involved in endomet rial carcinogenesis. Methods: We performed Western blot analysis of five ce ll-cycle stimulating (cyclins D1, E, B1, cdk2, cdk4) and three cell-cycle i nhibiting (p16(INK4a), p21(WAF1), Rb) proteins in 41 endometrial carcinoma specimens. In addition, expression of the estrogen and progesterone recepto rs (ER, PR), Ki67, and. in selected cases, p16, cyclin E, and cyclin BI was studied by immunohistochemistry. Results: We found upregulation of all ana lyzed cell-cycle regulators in most tumors compared to normal endometrial t issue samples. Overexpression of cyclin E, cyclin B1, and p21 was associate d with a less differentiated phenotype. In addition, high levels of cyclin E, cdk2, and cdk4 correlated with weak/absent ER expression, and p16 and p2 1 overexpression was significantly associated with low PR immunoreactivity. Cyclin BI expression correlated with cyclin E. cdk2, cdk4, p21, Rb, and Ki 67, and cyclin E expression with cyclin D1 and Rb. Conclusions: We conclude that cyclin E and cyclin B1 might be the major cell-cycle regulators invol ved in proliferation and reduced differentiation of endometrial carcinomas. In addition, p16, p21, and Rb appear to be uncoupled from their normal cel l-cycle inhibiting function in many endometrial carcinomas.