HMGA2 gene amplification and overexpression in human prolactinomas and the development of pituitary adenomas in HMGA2 transgenic mice showed that HMGA2 plays a crucial role in pituitary tumorigenesis. We have explored the pRB/E2F1 pathway to investigate the mechanism by which HMGA2 acts. Here we show 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, HMGA2-mediated E2F1 activation is a crucial event in the onset of these tumors in transgenic mice and probably also in human prolactinomas.

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Overexpression of the HMGA2 gene is a common feature of neoplastic cells both in experimental and human models. Intragenic and extragenic HMGA2 rearrangements responsible for HMGA2 gene overexpression have been frequently detected in human benign tumours of mesenchymal origin. To better understand the role of HMGA2 overexpression in human tumorigenesis, we have generated transgenic mice carrying the HMGA2 gene under the transcriptional control of the cytomegalovirus promoter. High expression of the transgene was demonstrated in all the mouse tissues analysed, whereas no expression of the endogenous HMGA2 gene was detected in the same tissues from wild-type mice. In this study, two indipendent lines of transgenic mice have been generated. By 6 months of age, 85% of female animals of both transgenic lines developed pituitary adenomas secreting prolactin and growth hormone. The transgenic males developed the same phenotype with a lower penetrance (40%) and a longer latency period (about 18 months). Therefore, these data demonstrate that the overexpression of HMGA2 leads to the onset of mixed growth hormone/ prolactin cell pituitary adenomas. These transgenic mice may represent an important tool for the study of this kind of neoplasia.

We have investigated the role of the NFkB complex in the process of thyroid carcinogenesis by analysing thyroid carcinoma cell lines. A signi®cant increase in p65 NFkB mRNA and protein expression, compared to normal thyroid cultures or tissue, was found in all of the cancer cell lines. Conversely, only a modest increase in the p50 NFkB mRNA and protein was found in most, but not all carcinoma cell lines. The block of p65 protein synthesis with speci®c antisense oligonucleotides greatly reduced the ability of two undierentiated carcinoma cell lines to form colonies in agar and reduced their growth rate. On the other hand, no eect was observed in the same cell lines when treated with p50 speci®c antisense oligonucleotides. These inhibitory eects seem to be mediated by the suppression of c-myc gene expression, since treatment with antisense oligonucleotides for p65 gene interfered negatively with c-myc gene expression. Our results indicate that activation of the NFkB complex by overexpression of p65 plays a critical role in the process of thyroid cell transformation.