Cushing disease is a life-threatening disorder most commonly triggered by tumors, often benign, in the pituitary glands, resulting in excess production of adrenocorticotrophic hormone (ACTH). The condition is marked by progressive weight gain, excessive fatty tissue deposits and a rounding of facial features, known as "moon face," and can lead to diabetes, hypertension, osteoporosis, obesity and psychological disturbances.
Cushing disease, which is more common in women than men, is also associated with a three- to four-fold increase in the risk of premature death. But what drives the tumor growth and the excess production of ACTH?
UCLA researchers and their colleagues have now found that testicular orphan nuclear receptor 4 (TR4) is overexpressed in the tumors. The scientists discovered that by knocking down TR4 in lab mice, they were able to reverse tumor growth and excess ACTH production.
The findings could potentially lead to a drug therapy for Cushing disease.
Study authors included Li Du, Marvin Bergsneider, Leili Mirsadraei, Steven H. Young, William H. Yong and Anthony P. Heaney of UCLA; Johan W. Jonker of the University of Groningen in the Netherlands; and Michael Downes and Ronald M. Evans of Gene Expression Laboratory at the Salk Insitute of Biological Studies in La Jolla, Calif.
The findings were published in the May 21 issue of the journal Proceedings of the National Academy of Sciences.
The research was supported by the National Institutes of Health (grants DK057978, HL105278, DK090962, HL088093, ES010337 and CA014195), the Helmsley Charitable Trust, the Samuel Waxman Cancer Research Foundation, UCLA's Jonsson Comprehensive Cancer Center, Ipsen/Biomeasure, the Human Frontier Science Program (grant CDA00013/2011-C), and the Netherlands Organization for Scientific Research (VIDI grant 016.126.338).