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Low Expression of the Cell Cycle Inhibitor p27^Kip1 in Normal Corticotroph Cells, Corticotroph Tumors, and Malignant Pituitary Tumors

Departments of Histopathology (K.L., S.J., D.G.L.) and Endocrinology (M.K., Z.K., G.K., P.J.J., J.P.M., G.M.B., A.B.G.), St. Bartholomew’s Hospital, London EC1A 7BE; Centre for Cell Molecular Medicine (R.N.C.), University of Keele, Stoke-on-Trent ST4 7Q3; and Ludwig Institute for Cancer Research (X.L.), St. Mary’s Hospital, London W2 1PG, United Kingdom

Address correspondence and requests for reprints to: Professor Ashley B. Grossman, Department of Endocrinology, St. Bartholomew’s Hospital, West Smithfield, London EC1A 7B, United Kingdom, E-mail: A.B.Grossman{at}mds.qmw.ac.uk

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-dependent kinase complexes, it regulates progression of G₁ to S phase in the cell cycle. It has been reported that p27 knockout mice develop multiorgan hyperplasia and intermediate lobe pituitary tumors secreting ACTH. Previously, we and others have been unable to show any consistent change in messenger RNA expression or genomic mutations for p27 in human corticotroph adenomas. However, dysregulation at the protein level has been reported in nonendocrine 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), Cushing’s disease (n = 21), acromegaly (n = 19), nonfunctioning adenomas (n = 18), prolactinomas (n = 7), TSH-omas (n = 2), FSH-omas (n = 6), aggressive tumors showing invasiveness and recurrence (n = 9), and metastatic pituitary carcinomas (n = 5). Using standard immunohistochemical techniques with a highly specific monoclonal antibody, p27 expression was determined quantitatively as the percentage of cells showing strongly positive, weak, or negative staining. In each sample, 500 cells were analyzed. We also analyzed normal pituitaries using double-labeling for p27 and each of the pituitary hormones to characterize the expression of p27 in each cell type. p27 was expressed in normal pituitary cells; in tumors expressing GH, prolactin, TSH, and FSH; and in aggressive tumors, but markedly reduced expression of p27 was seen in corticotroph tumors and pituitary carcinomas. In the normal pituitary, somatotroph, lactotroph, and thyrotroph cells showed strong p27 staining, whereas normal corticotroph cells showed a much lower level of p27 staining (P < 0.001). Somatotroph, lactotroph, gonadotroph, and thyrotroph adenomas showed a lower level of p27 expression compared with normal somatotrophs (P = 0.02), lactotrophs (P = 0.03), gonadotrophs (P = 0.01), and thyrotrophs, respectively, whereas the lower level of p27 expression present in normal corticotrophs virtually disappeared in corticotroph adenomas (P = 0.001).

We conclude that pituitary adenomas show a lower level of p27 protein expression than the normal cells from which they are derived, with malignant transformation leading to complete loss of p27 immunoreactivity. Corticotrophs are quite different to other pituitary cell types in terms of p27 immunoreactivity because both normal and tumorous corticotrophs have low p27 staining, and we speculate that this may relate to their inherent control mechanisms.

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