Reduced expression levels of the cell-cycle inhibitor p27(Kip1) in human pituitary adenomas

The molecular mechanisms leading to increased cellular proliferation rates and, thus, tumor formation in the anterior pituitary gland are poorly under stood. The cyclin-dependent kinase inhibitor p27(Kip1) is a key molecule re gulating the G1 phase of the cell cycle in many cell types. Furthermore, it was shown that p27 knock-out mice develop pro-opiomelanocortin-positive pi tuitary tumors. In an effort to clarify the role of p27 in the normal and t umorous human pituitary, we studied the expression of p27 by immunohistoche mistry, using a highly specific mouse monoclonal anti-human p27 antibody, N ormal pituitaries and 54 pituitary adenomas (twelve somatotrope adenomas, n ine prolactinomas, twelve corticotrope adenomas, three TSH-producing tumors , six gonadotrope adenomas, six null cell adenomas, and six oncocytomas) we re analyzed, p27 expression was determined semiquantitatively with regard t o both the percentage of positive cells and the intensity of the staining. Normal human pituitaries showed strong expression of p27 in most nuclei. In contrast, the levels of p27 were reduced in the majority of the tumors ana lyzed. Twenty-two tumors (six somatotrope adenomas, five prolactinomas, fou r corticotrope adenomas, two TSH-producing tumors, two gonadotrope adenomas , and three null cell adenomas) were completely p27-negative, In 18 tumors, p27 expression was found in less than or equal to 10% of the cells. In the other ten tumors, 11-80% of the cells were p27-positive. In summary, we we re able to demonstrate reduced expression levels of the cell-cycle inhibito r p27 in tumors derived from all pituitary cell types. Our data indicate th at p27 may be an important regulator of cellular proliferation in the anter ior pituitary, the underexpression of which could play a role in pituitary tumorigenesis.