Ovarian epithelial
tumors are classically divided into benign, malignant, and borderline or of low malignant potential. It is controversial whether this last group of
tumors should be considered benign or malignant. Expression of cell cycle markers has recently been linked to
tumor behavior and response to treatment. It has been shown that one of the pathways through which the p53 gene controls the cell cycle is by transactivating p21WAF1/CIP1, a
cyclin-dependent kinase (cdk) inhibitor. By inhibiting cdks, p21WAF1/CIP1 blocks the G-1 to S-phase transition in the cell cycle. p53 can be regulated by MDM2 (murine double minute-2) through direct inactivation or promotion of its cytoplasmic degradation. In an attempt to investigate the cell cycle checkpoint mechanisms of these
tumors, we studied the expression of p53, Ki-67, MDM2, and p21WAF1/CIP1 by immunohistochemistry. We analyzed the expression of these
proteins in 19
cystadenomas (8 serous and 11 mucinous), 40 borderline
tumors (31 serous and 9 mucinous), and 18 serous
carcinomas of the ovary. p21WAF1/CIP1 was expressed in 7 of 19 (37%) benign
cystadenomas, 32 of 40 (80%) borderline
tumors (93.5% of serous and 33% of mucinous), and in 9 of 18 (50%) serous
carcinomas. Ki-67 was only weakly expressed in 8 of 19 (42%) benign
cystadenomas, all borderline
tumors showed Ki-67 staining in less than 50% of the cells, and 55% of serous
carcinomas stained in more than 50% of
tumor cells. p53 was absent in all but 1 of the
cystadenomas, was expressed in 9 of 40 (22.5%) borderline
tumors (25.8% of serous and 11% of mucinous), and in 10 of 18 (55%)
carcinomas. All 11 implants of serous borderline
tumors expressed p21WAF1/CIP1. Most serous borderline
tumors expressed higher levels of MDM2 compared with the benign
cystadenomas and
carcinomas. Four of the serous borderline implants (40%) expressed MDM2. Coexpression of p21WAF1/CIP1 and MDM2 characterizes serous borderline
tumors of the ovary and their implants, which suggests that these cell cycle control
proteins are important in these
tumors and may be related to
tumor progression. Low expression of p53
protein in serous borderline
tumors might be in part mediated by MDM2. This suggests that the p53 pathway is intact in most of these
tumors, in contrast with
carcinomas, in which high expression of p53 has been related to mutations of this gene.