Identification of Growth arrest and DNA-damage-inducible gene beta (GADD45beta) as a Novel Tumor Suppressor in Pituitary Gonadotrope Tumors

Gonadotrope or null cell pituitary tumors present clinically with signs of hypogonadism and hypopituitarism, together with visual disturbances due to mass effects. Since there are no medical therapies, surgery and/or radiation are the only therapeutic options. To identify dysregulated genes and/or pathways that may play a role in tumorigenesis and/ or progression, molecular profiling was performed on 14 gonadotrope tumors and 9 normal human pituitaries from autopsy samples. Principle component analysis (PCA) revealed clear discrimination between tumor and normal pituitary gene expression profiles. Bioinformatic analysis identified specific genes and pathways that were highly differentially regulated, including a cohort of putative downstream effectors of p53 were repressed in gonadotrope pituitary tumors, including GADD45, GADD45 and Reprimo with concomitant downregulation of the upstream regulator, PLAGL1. PLAGL1 reexpression in gonadotrope cells did not directly modulate the downstream targets. Further functional analysis of GADD45 was performed. Overexpression of GADD45 in mouse gonadotrope cells blocked proliferation, increased rates of apoptosis in response to growth factor withdrawal and increased colony formation in soft agar. In contrast to prior studies with GADD45, methylation interference assays showed no evidence of epigenetic modification of the GADD45 promoter in pituitary tumors. Thus, our data suggest that many components downstream of p53 are suppressed in gonadotrope pituitary tumors. A novel candidate, GADD45 is low in tumors and reexpression blocks proliferation, survival and tumorigenesis in gonadotrope cells. Unlike GADD45, GADD45 is not methylated to block its expression. Together these studies identify new targets and mechanisms to explore concerning pituitary tumor initiation and progression.

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Michaelis KA, Knox AJ, Xu M, Kiseljak-Vassiliades K, Edwards MG, Geraci M, Kleinschmidt-DeMasters BK, Lillehei KO, Wierman ME