Molecular mechanism of human uterine endometrial carcinogenesis

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In the process of normal cell cycle, the cooperation of factors such as tumor suppressor gene products, cyclins, and cdks is essential. Abnormalities of the cooperation of these factors may result in malignant transformation of the cell. To examine the mechanism in the development of the endometrial carcinomas, we studied the immunohistochemical reactivity of these factors in endometrial carcinoma. The normal and hyperplastic endometria adjacent to carcinoma showed positive staining for ER,PR,but negative for p53. Of 59 carcinomas, 40 showed strongly positive staining for ER and PR,but negative for p53, while the other 19 showed negative staining for ER,PR,and positive for p53. The p53 positive staining was located just in the areas with negative staining for ER and PR.In the cancer cells with weak p53 staining, Rb staining were strongly positive and cyclin E staining were weakly positive. However, in the cancer cells with strong p53 staining, Rb staining was either weak or negative, b … More ut cyclin E staining was strongly positive. These data suggest that a stepwise abnormalities of sex steroid receptors, tumor suppressors, and cyclins seems to exist. The expression of cdk4 was observed in the proliferative phase of normal endometria as well as endometrial carcinomas, but the expression was not homogenous and preferentially observed in the nucleus of the endometrial carcinomas. Low expression of p16 was observed in the proliferative phase of normal endometria and in the endometrial carcinomas. The area with high expression of p16 showed low expression of cdk4, while the area with low expression of p16 showed high expression of cdk4. No cyclin D1 expressed in normal endometria, while high expression was observed in the nucleus of the endometrial carcinomas which are highly expressed of cdk4. These data suggest that inverse expression of p16 versus cdk4 and cyclin D1 is present in the human uterine endometrial carcinomas. Taken together, , our data suggest that a stepwise abnormalities of the tumor suppressor gene products, cyclins, and cdks may correlate with the advancement of malignancy in the development of the endometrial carcinoma. Less