Pituitary tumorigenesis in transgenic female mice expressing hCGbeta- subunit is mediated by upregulation of Cyclin D1, E2F1 and HMGA2 genes: a model for hormonally dependent prolactinomas.

AHTIAINEN P, RULLI SB, MAMAEVA V, RIVERO-MULLER A, ROYTTA M, HUHTANIEMI I.

Toronto, Canada

Congreso; 89th Annual Meeting of The Endocrine Society; 2007

The Endocrine Society

Recently, several genetically modified mouse models have been developed to assess the molecular mechanisms underlying the formation of prolactinomas. Aberrant expression of high mobility group A2 (Hmga2) gene has been shown to cause pituitary tumors in mice, and the same has also been found in human prolactinomas. We used recently developed transgenic (TG) mice expressing ubiquitously the human chorionic gonadotropin b-subunit (hCGb) to characterize the formation of lactotroph adenomas. These mice develop prolactinomas without overt hyperestrogenism but with highly elevated progesterone secretion. Formation of prolactinomas in TG females was completely inhibited by gonadectomy or by tamoxifen treatment, indicating a vital role of the normal estrogen levels in this process. Bromocriptine and mifepristone partially blocked the lactotroph hyperplasia indicating that disturbed dopaminergic tone and high level of progesterone participate in the pituitary tumorigenesis. More detailed analysis showed that cyclin D1 (Ccnd1) was upregulated 2-fold in 4.5 mo-old, 9-fold in 6 mo-old, and 11-fold in 12 mo-old TG pituitaries. Also, transcription factor E2f1 expression correlated with the expression of Ccnd1 suggesting the role of retinoblastoma (Rb) protein in tumorigenesis. This was further supported by immunohistochemical studies, which showed decreased nuclear Rb staining in TG females as compared with age-matched WT females. More importantly, Hmga2 was 3-fold upregulated in 6 mo-old and 8-fold in 12 mo-old TG pituitary tumors suggesting its role in formation of the TG prolactinomas, as has recently been shown in man and in mice. Pituitary Hmga2 expression correlated with serum leptin concentration, suggesting that the obesity seen in TG females may contribute to the pituitary tumorigenesis. The Hmga2 promoter contains Sp1 sites and leptin has been shown to regulate Sp1 activation through the Stat 3 pathway. In conclusion, our mice model offers a new tool to study the role of endocrine dysregulation in the formation of prolactinomas, especially through aberrant Ccnd1 and Hmga2 expression, and it may reveal the hormonal factors leading to aberrant Hmga2 expression also in human prolactinomas.