Deregulation of the pituitary Smad-independent Activin signalling promotes prolactinoma development

FARAONI, ERIKA YANIL; MARCIAL-LOPEZ, C AGUSTINA; DÍAZ -TORGA GRACIELA; PEÑA, MILAGROS; PEREZ, PABLO; GUTIERREZ, SILVINA; ABELEDO-MACHADO, ALEJANDRA; RULLI, SUSANA B

Mar del PLata

Congreso; Sociedad Argentina de Investigación Clínica; 2019

SAIC

Activins are known inhibitors of lactotroph function. Pit-1 is a pituitary-specific transcription factor that plays an important role in regulating PRL expression. Despite pSMAD2/3 is known as the activins-canonical intracellular signalling, it was described that activin represses Pit-1 expression in lactotroph cells in a Smad-independent mechanism.We have previously demonstrated that decreased pituitary activin expression is involved in prolactinoma development. In the present work we have studied the activin-signalling pathways involved. We used two different animal models of prolactinomas: female mice lacking dopamine type 2 receptor (Drd2-/-) and female mice overexpressing the β subunit of the human chorionic gonadotrophin (hCGβ+). We used wild-type (wt) mice as controls.Despite the reduced activin expression found in prolactinomas vs wt pituitaries, we found unexpectedly increased pSMAD3 expression (western blot) in prolactinomas. But nevertheless, by using double immunostaining, we observed that pSMAD3 co-localizes mainly in FSH+ cells, but not in PRL+ cells. Then we focused on the activin alternative pathway involved in prolactinoma development. Our results show that wt female pituitaries present high activin expression concomitant with strong expression of p-p38 in lactotroph population (double IHC). However, activin expression is decreased in prolactinomas concomitant with decreased p-p38 expression in PRL+ cells, increased Pit-1 mRNA expression (q-RT-PCR) and tumor development.This highlights the importance of the activin inhibitory action on lactotroph function and places the activin system and the p38 MAPK pathway as new targets in the treatment of dopamine agonist resistant prolactinomas.