Caracterización del Sistema TGF-β1 hipofisario: En búsqueda de un blanco terapéutico para prolactinomas resistentes a drogas dopaminérgicas.

MV RECOUVREUX; LARA LAPYCKYJ; MA CAMILLETTI; BECÚ-VILLALOBOS D; DIAZ DE TORGA, GRACIELA S

Buenoa Aires

Congreso; Sociedad Argentina de Biología; 2012

Sociedad Argentina de Biología

CHARACTERIZATION OF PITUITARY TGF-1 SYSTEM: IN THE SEARCH OF THERAPEUTIC TARGETS FOR RESISTANT PROLACTINOMAS Recouvreux MV, Lapyckyj L, Camilletti MA, Becú-Villalobos D, Díaz-Torga G. IBYME-CONICET Prolactinomas are benign adenomas usually treated with dopaminergic agonists. 15% of these tumors are resistant and there are no alternative therapies. As TGF-1 inhibits lactotrope proliferation, mediating dopamine (DA) inhibitory action, in this work we characterized pituitary TGF-1 system and the regulation of its components by DA and estradiol (E2), in order to evaluate their potential as therapeutic targets. We found the TGF-1 system down-regulated in our two experimental models of prolactinoma: female knock-out mice for dopamine D2 receptor and female rat chronically treated with E2. We found that DA and E2 regulate, not only synthesis, but also pituitary TGF-1 activation in vivo. We identified TSP1 and KLK1 as candidates to mediate TGF-1 activation induced by E2 and DA. We described, for the first time, the latent TGF-1 binding proteins expression in the pituitary. They are regulated by DA and E2, and differentially expressed in normal vs. tumoral pituitaries. Finally, we assayed the efficacy of an in vivo treatment with TSP1 mimetic peptides (ABT-510 and ABT-898). ABT treatment reduced prolactin serum levels and pituitary weight, effects mediated by their anti-angiogenic properties and by the recovery of active TGF-1 levels. Since TGF-1 exerts a negative control on lactotrope cells, recovering its local activity would be effective in inhibiting tumor growth of dopamine agonist resistant prolactinomas.