Expression of Glucocorticoid Receptor Gene Isoforms in Corticotropin-Secreting Tumors

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Abstract
The molecular basis of Cushing's disease is not known. One of the most characteristic features of such tumors is their resistance to corticosteroid feedback at the pituitary level. We have hypoth- esized that abnormalities of the glucocorticoid receptor (GR) gene might play a role in the development of Cushing's disease via an increase in the relative production of the nonligand-binding splice variant of the GR, GRb, known to exert dominant negative effects over the ligand-binding isoform, GRa. Alternatively, a change in overall GR expression, or mutations of some functional domains of the GR gene, might be involved in the pathogenesis of corticotroph tumors. We studied 22 tumors (17 pituitary ACTH-secreting tumors, 2 ectopic ACTH-producing tumors, 2 prolactinomas, and 1 nonfunc- tioning adenoma) and three normal pituitaries. RT-PCR was per- formed with primers specific to GRa and GRb complementary DNA, followed by Southern blotting using an internal probe, and the ratio of the two bands quantitated by densitometry. We also assessed the overall expression of GR relative to the message of both the POMC gene and a housekeeping gene. Single-strand conformation polymor- phism analysis of the DNA-binding domain and splice junction region of the gene was also performed. GRa messenger RNA was expressed at 37.3-fold 6 5.7 (range, 32 to 46) excess, as compared with the GRb subform. This pattern was observed both in the tumor samples and in the normal pituitaries used as controls. A majority of the ACTH-secreting tumors (16/19), includ- ing the ectopic secretors, showed variable but increased overall GR expression, whereas 3 tumors showed an expression approximately equivalent to the normal controls; however, no correlation was found between these two groups and the response to the high-dose dexa- methasone test, nor was there any correlation with tumor histology. No mutations were found in any of the tumors by PCR-single-strand conformation polymorphism analysis. In conclusion, although both pituitary and ectopic ACTH-secreting tumors are at least partially glucocorticoid-resistant, no significant abnormalities in the relative expression of the two main GR subforms were observed in a series of such tumors. Additionally, mutations of regions critical to normal function of the receptor do not seem to be a frequent event in these tumors. (J Clin Endocrinol Metab 82: 1088 - 1093, 1997)

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