GISNe - Anatomia, Farmacologia e Medicina Legale

RETINOIDS AND DOPAMINE RECEPTOR SUBTYPE 2 EXPRESSION IN HUMAN
SECRETING AND NON SECRETING ADENOMAS
Bondioni S., A.R.Angioni, G. Mantovani, M.Locatelli * , P. Rampini * , S. Ferrero § , E.Ferrante,
P.Beck-Peccoz, A.Spada, A.G.Lania.
Dept. of Medical Sciences, Endocrine-Metabolic Unit, University of Milan, Fondazione Ospedale
Maggiore IRCCS Milano, *Dept.of Neurosurgery, Fondazione Ospedale Maggiore IRCCS Milano;
§ Pathology Unit, Dept of Medicine, Surgery and Dentistry, A. O. San Paolo, Milan.
It has been demonstrated that dopamine receptor subtype 2 (DR2) promoter contains a functional
retinoic acid response element possibly involved in the control of DR2 expression as demonstrated
by the low DR2 protein levels in animal models lacking this regulatory domain. Aim of the study
was to evaluate the effect of 9-cis-retinoic acid (RA) treatment on DR2 expression in 16 human
secreting and non-secreting pituitary adenomas (9 NFPA, 5 GH-omas, 2 PRL-omas). In basal
conditions, variable levels of D2R protein were detected by immunoblotting in most tumors,
without significant differences between NFPA and GH-omas. Conversely, the signal was absent in
the two PRL-omas investigated. Cell exposure to RA (100 nM) increased DR2 protein levels in 5/9
NFPA and 3/5 GH-omas, while no modification were observed in PRL-omas. These data were
further confirmed at the mRNA levels since in non-responder tumors, RA treatment did not affect
DR2 mRNA levels. Immunohistochemistry showed a homogeneous pattern of retinoic acid receptor
RXRα, RXRβ and RXRγ isoforms expression without any correlations with the induction of DR2,
thus suggesting that the absent D2R induction by RA in individual tumors was not related to RA
receptor deficiency. Finally, RA did not significantly modify in vitro GH release from 3 cultured
GH-omas, while induced a 67% stimulation of PRL release from the prolactinoma. In conclusion,
the study showed that D2R was induced by RA in a consistent number of pituitary tumors,
suggesting the existence of interaction between RA and D2R in human pituitary cells. However, the
main goal of the study, i.e. the induction of D2R expression in prolactinomas, the tumor type that
recognizes loss of D2R as a major cause of unresponsiveness to medical therapy, was not achieved.