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AKT Is Highly Phosphorylated in Pheochromocytomas But Not in Benign Adrenocortical Tumors

Endocrine and Diabetes Unit (M.F., D.W., S.E., M.Z., S.H., B.A.), Department of Internal Medicine I, and Institute of Pathology (P.A.), University of Würzburg, 97080 Würzburg, Germany; and Endocrine and Diabetes Unit (F.B.), Department of Medicine II, University of Freiburg, 179106 Freiburg, Germany

Address all correspondence and requests for reprints to: Dr. Martin Fassnacht, Department of Medicine, Endocrine and Diabetes Unit, University of Würzburg, 97080 Würzburg, Germany. E-mail: Fassnacht_m{at}medizin.uni-wuerzburg.de.

Context: Activation of AKT plays a major role in a variety of human neoplasias. In mice, a heterozygous deletion of the Pten gene is associated with increased activation of AKT and with development of pheochromocytomas.

Objective: The objective of this study was the investigation of the role of AKT in the pathogenesis of pheochromocytomas and adrenocortical tumors.

Design, Setting, and Participants: Total AKT and phosphorylated AKT (pAKT) in 15 pheochromocytomas, nine aldosterone-producing adenomas, nine cortisol-producing adenomas, eight adrenocortical carcinomas (ACC), and 15 normal adrenals were investigated by Western blot analysis. Immunohistochemistry for total AKT and pAKT was performed in pheochromocytomas (n = 8), ACC (n = 4), and normal adrenal glands (n = 2). In addition, in pheochromocytomas PTEN protein expression and PTEN loss of heterozygosity were analyzed.

Main Outcome Measures: Determination of pAKT/total AKT ratio in adrenal tissues was the main outcome.

Results: In comparison to normal adrenals, total AKT expression was elevated in both pheochromocytomas (193 ± 22%) and ACC (176 ± 36%). The pAKT/AKT ratio was significantly increased in pheochromocytomas (338 ± 49% vs. 100 ± 11%) but not in ACC, aldosterone-producing adenomas, and cortisol-producing adenomas. No loss of heterozygosity of PTEN and no decrease in PTEN protein was detected in pheochromocytomas. Immunohistochemistry showed strong and homogeneous AKT and pAKT staining in pheochromocytomas and focal staining in ACC.

Conclusion: Our findings provide evidence for increased activation of AKT in pheochromocytomas but not in adrenocortical adenomas.