Aberrant expression of G(1)/S regulators is a frequent event in sporadic pituitary adenomas

Components of the pRb/p16/cyclin D1/CDK4 pathway are frequent targets in nu merous tumour types, including those of pituitary origin. However, previous studies of pituitary tumours have examined individual components of this p athway. Therefore, to determine their overall contribution we have simultan eously examined the immunohistochemical status of pRb, p16 and cyclin DI an d analysed the CDK4 gene for a characterized activating mutation. Of the to tal pituitary tumour cohort (29 clinically non-functioning adenomas and 16 somatotrophinomas) abnormal expression of either pRb, p16 or cyclin D1 was observed in 36 of 45 (80%) tumours and was significantly (P = 0.005) associ ated with non-functioning tumours (27/29; 93%) compared with somatotrophino mas (9/16, 56%). Loss of either pRb or p16 expression was mutually exclusiv e in 23 of 45 (51%) tumours, whilst concomitant loss of pRb and p16 express ion was observed in five tumours. Cyclin DI overexpression was observed in 22 of 45 (49%) tumours, however, there was no significant association betwe en overexpression of cyclin DI and the expression status of either pRb or p 16. In addition, no activating mutations within codon 24 of the CDK4 gene w ere detected. This study provides evidence for the first time that, compone nts of the pRb/p16/cyclin D1/CDK4 pathway, either alone or in combination, are frequently deregulated in human pituitary tumours, suggesting that this pathway may be a useful target in drug or gene therapeutic approaches.