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Research on the Molecular Mechanism of Cushing’s Disease

Cushing disease is caused by pituitary tumors that produce excessive amounts of the pituitary hormone ACTH, leading to excessive synthesis of glucocorticoids by the adrenal glands. Many symptoms of Cushing disease result from these high levels of glucocorticoids and they include fat accumulation, high blood pressure and predisposition to diabetes and osteoporosis. Normally when blood glucocorticoids are elevated, they exert a negative feedback effect on the production of pituitary ACTH, thus closing a regulatory loop that keeps both ACTH and glucocorticoid levels in balance. The hallmark of the pituitary corticotroph adenomas that cause Cushing disease is that these tumor cells are no longer sensitive to the feedback action of glucocorticoids. This hormone resistance is likely the first event in the formation of the pituitary tumors. A Montréal research group led by Dr. Jacques Drouin and including collaborators in Canada, France, the Netherlands and United States has just discovered essential components of the molecular mechanism for glucocorticoid feedback control of pituitary ACTH gene expression. Indeed, the Montréal group discovered a large complex made of several proteins that are essential for negative feedback by glucocorticoids; this complex includes proteins that are known for their role in the control of gene expression and remodeling of chromosome (chromatin) structure. One of these essential proteins, BRG1, is also known to be a tumor suppressor. Consistent with the essential functions of these proteins in negative feedback by glucocorticoids, the researchers found that either of these proteins is no longer correctly expressed in about half of pituitary tumors from Cushing disease patients (both adult and pediatric) as well as from dogs with Cushing disease (for unknown reasons, this condition is more frequent in dogs than humans), thus providing a molecular explanation for the hormone resistance that characterizes theses tumors.

This work brings the first molecular insight into the mechanisms of Cushing disease. Beyond explaining hormone resistance, it also identified genes that likely initiate the process of tumor formation. This novel insight will lead to the rationale design of new therapeutic approaches for the more efficient management of patients with Cushing disease.

Editor’s Note: This work is published in the 15 October issue of Genes and Development (Bilodeau et al, Genes Dev 2006, 20:2871-2886) and it was supported by grants from the National Cancer Institute of Canada and from the Canadian Institutes of Health Research.

 

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