Characterization of the hormonal requirements and molecular mechanisms that underlie pituitary tumorigenesis in mice overexpressing luteinizing hormone

The majority of pituitary adenomas in humans are non-metastasizing, monoclonal neoplasms that occur in approximately 20% of the general population. Their development has been linked to a combination of extrinsic factors and intrinsic defects. We now demonstrate that targeted and chronic overexpression of luteinizing hormone (LH) in transgenic mice (LHCTP) causes ovarian hyperstimulation and subsequent development of functional pituitary adenomas involving lactotropes, somatotropes, and thyrotropes. Tumors fail to develop in ovariectomized mice indicating that contributions from the ovary are necessary for adenoma development. We have found that ovariectomy followed by estrogen replacement results in expansion of lactotropes selectively in LH overexpressing mice.; The selective response of LHCTP pituitaries to the tumorigenic effects of estrogen suggested that intrinsic defects likely contribute to adenoma development. To characterize gene expression changes associated with development of pituitary adenomas, we have performed microarray studies and compared expression profiles from pituitary tumors in LHCTP mice to wild-type controls. We have identified a number of candidate genes with altered expression in pituitary tumors. One gene in particular, p8 (Com-1), was highly induced in pituitary adenomas. p8 encodes a putative HMGA-like transcription factor that has previously been shown to be necessary for transformation of mouse embryonic fibroblasts and has also been implicated in breast cancer progression. We have shown that p8 is localized to tumor foci containing lactotropes, suggesting that p8 may be important in the transformation of these cells. To demonstrate the functional significance of p8 in pituitary tumorigenesis, we have generated stable GH3 (somato-lactotrope) cell lines with altered p8 expression. Tumors appear earlier and are larger in volume in nude mice injected with GH3 cells overexpressing p8 relative to control GH3 cells. Conversely, nude mice injected with GH3 cells that have reduced p8 expression have an attenuation in tumor development. Together, our data expand current models of pituitary tumorigenesis by suggesting that chronic ovarian hyperstimulation may underlie formation of a subset of pituitary adenomas containing lactotropes, somatotropes and thyrotropes and that a new HMGA family member, p8, may be involved in the intrinsic events leading to tumorigenesis.