New mechanisms involved in pathogenesis of prolactinomas: critical role of the HMGA genes
HMGA2 gene amplification and overexpression in human prolactinomas and development of pituitary adenomas in HMGA-transgenic mice showed that HMGA proteins play a crucial role in pituitary tumorigenesis. Recently, we have explored the pRB/E2F1 pathway to investigate the mechanism by which HMGA proteins act, showing that HMGA2 interacts with pRB and induces E2F1 activity in mouse pituitary adenomas by displacing HDAC1 from the pRB/E2F1 complex a process that results in E2F1 acetylation. We found that loss of E2F1 function (obtained by mating HMGA2 and E2F1−/− mice) suppressed pituitary tumorigenesis in HMGA2 mice, thus demonstrating that HMGA2-mediated E2F1 activation is a crucial event in the onset of these tumors.
To identify other genes involved in the process of pituitary tumorigenesis induced by the HMGA proteins, more recently we have analysed the gene expression profile of pituitary adenomas developed by HMGA2- and HMGA1-transgenic mice in comparison with normal pituitary glands from control mice. We have identified 82 transcripts increased and 72 transcripts decreased of at least 4-fold in all the mice pituitary adenomas analyzed compared with normal pituitary glands. Among these genes, we focused our attention on two genes, Mia/Cd-rap and Ccnb2, the first down- and the latter up-regulated in the adenomas compared to normal tissue. We demonstrated that the HMGA proteins directly bind to the promoter of both these genes and are able to regulate their expression.
For Ccnb2, the gene coding for cyclin B2, we also analysed the expression of its human homologue in a panel of human pituitary adenomas of different histotype and correlated the results with the expression of the HMGA genes. We found a statistical direct correlation between CCNB2 expression and each of the HMGA genes, thus indicating that HMGA-induced cyclin B2 overexpression gives an important contribution to human pituitary tumorigenesis.