HEPARIN-BINDING SECRETORY TRANSFORMING GENE (HST) FACILITATES RAT LACTOTROPE CELL TUMORIGENESIS AND INDUCES PROLACTIN GENE-TRANSCRIPTION

We have shown previously that human prolactinomas express transforming sequences of the heparin-binding secretory transforming gene (hst) wh ich encodes fibroblast growth factor-4 (FGF-4), To elucidate the role of hst in pituitary tumorigenesis we treated primary rat pituitary and pituitary tumor cell cultures with recombinant FGF-4 and also stably transfected pituitary cell lines with full-length human hst cDNA, Tran sfectants were screened for hst mRNA expression and FGF-4 production. FGF-4 (0.1-50 ng/ml) caused a dose-dependent 2.5-fold increase of prol actin (PRL) secretion (P < 0.001) in GH4 cells and up to 60% (P < 0.05 ) in primary cultures, while decreasing growth hormone release (P < 0. 001). GH4 hst transfectants displayed markedly enhanced basal PRL secr etion (threefold, P < 0.001) and also proliferated faster (P < 0.001). FGF-4 treatment of wild-type GH4 cells, transiently transfected with an expression construct (rPRL.luc) containing a luciferase reporter dr iven by the rPRL promoter, resulted in a dose-dependent increase of up to 3.3-fold in PRL transcriptional activity. Tumors derived from in v ivo subcutaneous injection of GH4 hst-transfected cells strongly expre ssing FGF-4 grew more aggressively as assessed by histologic invasiven ess and proliferating cell nuclear antigen staining (P < 0.01), The re sults indicate that hst overexpression mediates lactotrope tumor growt h and potently stimulates PRL synthesis, Thus, hst may directly facili tate prolactinoma development via paracrine or autocrine action of its secreted protein, FGF-4.