Wnt/Beta-Catenin signaling in murine and human prolactinomas

DEMARCHI GIANINA; GAZZA ELIAS; PERRONE SOFIA; TORRES MA.JOSÉ; BERNER SILVIA; CRISTINA CAROLINA

Banff

Simposio; Keystone Symposia on Molecular and Cellular Biology, Developmental Pathways and Cancer: Wnt, Notch and Hedgehog; 2014

Keystone

Pituitary adenomas constitute 10% of intracranial tumors. They cause morbidity and mortality due to critical localization, hormone secretion and expansion, affecting cerebral functions. Prolactinomas are the most frequent pituitary adenomas. Dysregulation of Wnt pathway is related to carcinogenesis. We aimed to characterize Wnt pathway in experimental and human prolactinomas in relation to beta-catenin expression to determine its role in tumor development. We generated experimental prolactinomas in female mice by chronic administration of the dopaminergic antagonist Haloperidol (Halop) or Estradiol (E2) during 3 weeks and analyzed beta-catenin expression and localization by immunohistochemistry. A marginal increase in nuclear localization (p=0.085 E2; p=0.083 Halop) and a reduction of beta-catenin in the membrane (p=0.048 E2 p=0.101 Halop) were observed in treated pituitaries compared to controls. Beta-catenin mRNA levels were unaltered after treatment. There was an increase in Wnt5a (p=0.038 E2. p=0.087 Halop vs control) and a reduction in Frizzled8 mRNA levels. Lrp6 did not change with any treatment and Tcf4 levels decreased with E2 (p= 0.047). Neither the target gen Pitx2 nor Ciclin D1 changed with Halop or E2. Interestingly, in primary pituitary culture, 10-8M E2 raised Beta-Catenin, Frizzled8 and Cyclin D1 mRNA levels.   Immunohistochemistry of beta-catenin in human prolactinoma paraffin sections showed clustered cells with membrane and cytoplasm staining. Because of beta-catenin relocalization in murine treated pituitaries, we conclude that the canonical Wnt pathway could be involved in experimental prolactinoma generation. Accordingly, we found changes in mRNA levels of Wnt pathway components after treatment both in vivo and in vitro. Furthermore, our results in human prolactinomas showed beta-catenin expression suggesting canonical Wnt pathway participation in prolactinoma development.