Identification of Growth Arrest and DNA-Damage-Inducible Gene β (GADD45β) as a Novel Tumor Suppressor in Pituitary Gonadotrope Tumors

Gonadotrope and null cell pituitary tumors cause significant morbidity, often presenting with signs of hypogonadism together with visual disturbances due to mass effects. Surgery and radiation are the only therapeutic options to date. To identify dysregulated genes and pathways that may play a role in tumorigenesis and/or progression, molecular profiling was performed on 14 gonadotrope tumors, with nine normal human pituitaries obtained at autopsy serving as controls. Bioinformatic analysis identified putative downstream effectors of tumor protein 53 (p53) that were consistently repressed in gonadotrope pituitary tumors, including RPRM, P21, and PMAIP1, with concomitant inhibition of the upstream p53 regulator, PLAGL1(Zac1). Further analysis of the growth arrest and DNA damage-inducible (GADD45) family revealed no change in the p53 target, GADD45 alpha, but identified repression of GADD45 beta in pituitary tumors in addition to the previously reported inhibition of GADD45 gamma. Overexpression of GADD45 beta in L beta T2 mouse gonadotrope cells blocked tumor cell proliferation and increased rates of apoptosis in response to growth factor withdrawal. Stable gonadotrope cell transfectants expressing increased GADD45 beta showed decreased colony formation in soft agar, confirming its normal role as a tumor suppressor. Unlike previous studies of GADD45 gamma in pituitary tumors and alpha and beta in other tumors, bisulfite sequencing showed no evidence of hypermethylation of the GADD45 beta promoter in human pituitary tumor samples to explain the repression of its expression. Thus, GADD45 beta is a novel pituitary tumor suppressor whose reexpression blocks proliferation, survival, and tumorigenesis. Together these studies identify new targets and mechanisms to explore in pituitary tumor initiation and progression. (Endocrinology 152: 3603-3613, 2011)