Apoptosis and apoptosis-related factors Bcl-2, Bax, tumor necrosis factor-α, and NF-κB in human endometrial hyperplasia and carcinoma

BACKGROUND. Apoptosis controls cell homeostasis in the endometrium during normal menstrual cycles, and morphologic studies have suggested its association with the development of endometrial carcinoma. Apoptosis is regulated by several genes, especially those of the Bcl-2 gene family, but their significance in endometrial pathologies is not well understood. METHODS. To study the role and regulation of apoptosis in endometrial hyperplasia and carcinoma, human endometrial specimens were analyzed using in situ 3'-end labeling of apoptotic cells and in situ hybridization and immunohistochemistry of apoptosis-related factors. RESULTS. Apoptosis was scarce in normal proliferating endometrium as well as in simplex, complex, and atypical hyperplasia and was low in Grade I adenocarcinoma. In Grade II adenocarcinoma a significant increase in the rate of apoptosis was observed. Apoptosis decreased in Grade III adenocarcinoma, but it was still higher than in normal or hyperplastic endometrium. Bcl-2 and Bax were expressed in normal and hyperplastic endometrium, and the Bcl-2/Box ratio was lower in endometrial carcinoma. Tumor necrosis factor-alpha was expressed in normal endometrium and simplex and complex hyperplasia, but it was down-regulated in atypical hyperplasia and endometrial carcinoma. The transcription factor NF-kappaB was present in proliferating endometrium and in endometrial hyperplasia, but its expression was lower in carcinoma. CONCLUSIONS. In endometrial proliferation and hyperplasia a low rate of apoptosis is present. In Grade I carcinoma the rate of apoptosis is decreased, but the rate is subsequently increased in advanced carcinoma. The decrease in the rate of apoptosis in Grade III adenocarcinoma may reflect loss of control of cell homeostasis, decreased differentiation, and increased malignancy.