The
cyclic AMP (cAMP) pathway plays a major role in the development of endocrine tissues and various molecular defects of key components of this pathway (
G protein, receptors, PKA, ...) have been observed in endocrine
tumors. Hypersecretion of
adrenocorticotropin hormone (
ACTH), the key activator of the cAMP pathway in adrenal cortex, is associated with adrenocortical
hyperplasia and
cortisol oversecretion (
Cushing's syndrome). The best example of "illegitimate" membrane receptors expression reported is the abnormal expression of the
adenylyl cyclase activating gastric inhibitory
peptide receptor (GIP-R) in
ACTH-independent
Cushing's syndrome (ACS). We have observed that ectopic expression of the GIP-R is frequent in
ACTH-Independent Macronodular Adrenal Hyperplasia (
AIMAH), rare in benign adrenal
adenoma (AA), but seems absent in
Adrenal Cancer (AC). In vivo systematic screening of
AIMAH shows at least one abnormal response of
cortisol (suggesting "illegitimate" membrane receptor expression) in almost all patients. Somatic and germ line inactivating mutations of PRKAR1 (regulatory subunit R1A of PKA) can be observed in patient with isolated primary pigmented nodular adrenocortical disease (PPNAD) and AA responsible for ACS. At the nuclear level, the cAMP pathway regulates transcription mainly by PKA-dependent phosphorylation of the
cyclic AMP response element binding (CREB) family of
transcription factors (CREB, CREM, and ATF-1).
Cyclic AMP response element binding protein (CREB) is expressed in normal adrenal cortex. Alterations of CRE
binding proteins with loss of CREB expression and compensatory overexpression of CREMtau is observed in the human
adrenocortical cancer cell line H295R. Similar alterations are found at the
protein level in human malignant adrenocortical
tumors. In conclusion, various alterations leading to activation or inactivation of key components of the cAMP signaling pathway can be observed in adrenocortical
tumorigenesis.