Low expression of the cell cycle inhibitor p27(Kip1) in normal corticotroph cells, corticotroph tumors, and malignant pituitary tumors

The cell cycle is regulated by a number of inhibitors, including p27(Kip1) (p27), which belongs to the kip1 family. By binding to the cyclin/cyclin-de pendent kinase complexes, it regulates progression of G(1) to 8 phase in th e cell cycle. It has been reported that p27 knockout mice develop multiorga n hyperplasia and intermediate lobe pituitary tumors secreting ACTH. Previo usly, we and others have been unable to show any consistent change in messe nger RNA expression or genomic mutations for p27 in human corticotroph aden omas. However, dysregulation at the protein level has been reported in none ndocrine tumors, and we, therefore, investigated the expression of p27 in a range of benign and metastatic pituitary tumors. We studied a total of 107 pituitaries, including normal pituitary (n = 20), Gushing's disease (n = 2 1), acromegaly (n = 19), nonfunctioning adenomas (n = 18), prolactinomas (n = 7), TSH-omas (n = 2), FSH-omas (n = 6), aggressive tumors showing invasi veness and recurrence (n = 9), and metastatic pituitary carcinomas (n = 5). Using standard immunohistochemical techniques with a highly specific monoc lonal antibody, p27 expression was determined quantitatively as the percent age of cells showing strongly positive, weak, or negative staining. In each sample, similar to 500 cells were analyzed. We also analyzed normal pituit aries using double-labeling for p27 and each of the pituitary hormones to c haracterize the expression of p27 in each cell type. p27 was expressed in n ormal pituitary cells; in tumors expressing GH, prolactin, TSH, and FSH; an d in aggressive tumors, but markedly reduced expression of p27 was seen in corticotroph tumors and pituitary carcinomas. In the normal pituitary, soma totroph, lactotroph, and thyrotroph cells showed strong p27 staining, where as normal corticotroph cells showed a much lower level of p27 staining (P < 0.001). Somatotroph, lactotroph, gonadotroph, and thyrotroph adenomas show ed a lower level of p27 expression compared with normal somatotrophs (P = 0 .02), lactotrophs (P = 0.03), gonadotrophs (P = 0.01), and thyrotrophs, res pectively, whereas the lower level of p27 expression present in normal cort icotrophs virtually disappeared in corticotroph adenomas (P = 0.001). We conclude that pituitary adenomas show a lower level of p27 protein expre ssion than the normal cells from which they are derived, with malignant tra nsformation leading to complete loss of p27 immunoreactivity. Corticotrophs are quite different to other pituitary cell types in terms of p27 immunore activity because both normal and tumorous corticotrophs have low p27 staini ng, and we speculate that this may relate to their inherent control mechani sms.