Critical role of the RB-E2F pathway in the generation of pituitary adenomas in transgenic mice overexpressing the HMGA2 gene

The HMGA2 protein plays a crucial role in the development of malignant and benign tumors through a mechanism still unknown. We have recently developed transgenic mice, which overexpress high levels of HMGA2 in all tissues. The large majority (85%) of female transgenic mice developed pituitary adenomas secreting prolactin (PRL) and growth hormone (GH) by the age of 6 months. This is consistent with our recent results showing amplification and overexpression of the HMGA2 gene in a large set of human prolactinomas. To investigate the mechanism by which HMGA2 is involved in pituitary tumorigenesis, we explored the RB/E2F pathway, both in vitro and in vivo, since RB has been shown to be implicated in pituitary tumorigenesis in animal models through a mechanism that involves the activation of E2F1. In our work, we demonstrate that HMGA2 interacts with RB and inhibits its growth suppressing function. Moreover, we show that the HMGA2 protein displaces HDAC1 from the RB/E2F complex in vitro and from the E2F target promoters in vivo, and enhances E2F1 activity. These findings indicate the existence of a pathway of RB regulation involving HMGA2. To validate the hypothesis that the increased E2F activity may be responsible for the onset of pituitary adenomas in HMGA2 mice, we have crossed HMGA2 mice with E2F1–/– mice. The resulting double mutant mice showed a significant reduction of the pituitary phenotype compared to the HMGA2 mice, indicating the critical role of the HMGA2-mediated enhancement of the E2F1 activity in the onset of these neoplasias.