Mdm2 and the p53 pathway in human pituitary adenomas

OBJECTIVE Studies on pituitary tumours have failed to identify mutations in the tumour suppressor gene p53 suggesting that the protein identified is w ild type. p21(WAF-1) is a downstream effector of p53 which promotes growth arrest. Mdm2 (mouse double minute) is a protein induced by wild type p53 an d forms an autoregulatory feedback loop suppressing wild type p53 activity. The purpose of this study was to examine a group of pituitary tumours for expression of p53 and its two downstream effector proteins p21(WAF-1) and m dm2 and to compare this with their radiological invasive status and prolife rative potential as assessed by Ki-67 expression. SUBJECTS and METHODS Sixty-nine tumours removed at transsphenoidal surgery were examined by immunocytochemistry using antibodies against p53, p21(WAF- 1), mdm2 and Ki-67 (MIB-1). The invasive status of the tumours was determin ed from the preoperative CT/MRI scans. RESULTS p53 was expressed in 42 of 69 (61%) pituitary adenomas but there wa s no relationship with either pituitary tumour invasive status (P = 0.71) o r volume (P = 0.33). p53 expression correlated, however, with the prolifera tive state of the tumours as assessed by the MIB-1 labelling index (P = 0.0 085). Invasive tumours had a higher growth fraction than non-invasive ones (P = 0.027). p21(WAF-1) was expressed in the nuclei of 58/69 (84%) pituitar y adenomas and its expression correlated with that of p53 (r = 0.26, P = 0. 03). Mdm2 was expressed in the cytoplasm of 46/69 (67%) tumours and this co rrelated with the nuclear staining for p53 (P = 0.022) while nuclear staini ng was seen in 32/69 (46%) tumours but this did not correlate significantly with nuclear p53 staining (P = 0.096). CONCLUSIONS These results suggest that p53, p21(WAF-1) and mdm2 are all exp ressed in pituitary tumours suggesting that the p53 protein detected by imm unocytochemistry is wild type. Expression of p53 is associated with tumours which have a higher proliferative status. The p53 activity is probably the result of upstream signals of local stresses mediated through either genet ic change, cytokines, hypoxia or hormonal factors. Our results suggest, how ever, that the downstream pathway mediated through the activities of p21WAF -1 and mdm2 may be dysfunctional in these tumours.