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Transcription Factor 3',5'-Cyclic Adenosine 5'-Monophosphate-Responsive Element-Binding Protein (CREB) Is Decreased during Human Adrenal Cortex Tumorigenesis and Fetal Development

Department of Endocrinology (D.R., L.G., E.J., K.P., S.M., X.B., J.B.), Institut Cochin, Institut National de la Santé et de la Recherche Médicale U576, René Descartes-Paris V University, 75014 Paris, France; Internal Medicine Unit (D.R.), École Nationale Vétérinaire d’Alfort, 94704 Maisons Alfort; Pathology Laboratory (A.L.), CHU Cochin, 75014 Paris, France; and COMETE Network (L.G., J.B., A.L., X.B., J.B.), France

Address all correspondence and requests for reprints to: Prof. Jérôme Bertherat, Service des Maladies Endocriniennes et Métaboliques, Hôpital Cochin, 27 rue du Fg-St-Jacques, 75014 Paris, France. E-mail: jerome.bertherat{at}cch.ap-hop-paris.fr.

Various cellular and molecular alterations of the cAMP pathway have been observed in adrenal Cushing syndrome. We recently reported the loss of cAMP-responsive element-binding protein (CREB) expression in the adrenocortical cancer cell line H295R. CREB is the major nuclear target of the cAMP pathway. This study therefore aimed to analyze the status of the CREB protein in various types of human adrenocortical tumors and normal fetal adrenal cortex. CREB protein status was studied by Western blotting in adrenocortical adenomas (AAs, n = 27) and adrenocortical carcinomas (ACs, n = 24). A decrease of CREB protein was noticed in the majority of the adrenocortical tumors. The dramatic decrease in CREB protein levels was more pronounced in ACs than in AAs. Levels of the phosphorylated form of CREB were also low in adrenocortical tumors, with a greater decrease in ACs than in AAs. EMSAs also showed decreases in the amounts of CREB- containing complexes in nuclear extracts from adrenocortical tumors. The secretory status of adenomas was strongly correlated with CREB levels, significantly lower in nonfunctioning AAs (n = 9) than in functioning AAs (n = 9). CREB levels, determined by Western blotting and immunohistochemistry, were very low in the fetal zone of human fetal adrenal cortex, whereas they were normal in the definitive zone. In tumors, adrenocortical cells in several zones were weakly immunohistochemically stained for CREB, whereas CREB was uniformly detected in nonendocrine cell nuclei (e.g. vascular cells, fibroblasts). These results suggest that the absence of CREB may be linked to the development of a highly aggressive tumor with a dedifferentiated benign (nonfunctioning AA) or malignant (AC) phenotype. These findings highlight the similarities between the normal human fetal adrenal gland and adrenal cancers previously observed in terms of parallelism in IGF-II production.

This work was supported in part by the Plan Hospitalier de Recherche Clinique (AOM 95201 to the Comete Network coordinated by Prof. P. F. Plouin and dedicated to the study of adrenal tumors) and the Association pour la Recherche sur le Cancer (ARC 4225).

Abbreviations: AA, Adrenocortical adenoma; Ab, antibody; AC, adrenocortical carcinoma; AU, arbitrary unit; CD, Cushing disease; CREB, cAMP-responsive element-binding protein; HRP, horseradish peroxidase; NAC, normal adrenal cortex; P, pheocromocytoma; P-CREB, phosphorylated CREB; SF-1, steroidogenic factor 1.

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