A ?Yin Yang" relationship between Estrogen Receptor α and β on PTEN/PI3K/Akt in the pituitary tumoral proliferation

JONATHAN TOLEDO, PABLO A. PÉREZ, FLORENCIA PICECH, LILIANA DV. SOSA, JUAN P. PETITI, JORGE H. MUKDSI, ANA L. DE PAUL, ALICIA I. TORRES, SILVINA GUTIÉRREZ

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

Sociedad Argentina de Investigación Clínica

Abstract: Previously it was shown that estrogen receptor (ER) βincreased the tumoral suppressor PTEN expression to modify thelactotroph and somatotrophs population growth and adequately respondto cyclic PRL y GH requirement during the estrous cycle. Expandingthese investigations, the aim of this work was to analyze theERα and β effects on PTEN/PI3K/Akt in the pituitary tumoral growthregulation mechanisms.To carry out this objective, female rats treated with estradiol benzoateduring 20, 40 and 60 days (hyperplasic/adenomatous pituitarymodel) and transfected GH3 tumoral cells (GH3 ERα+/ERβ- andGH3 ERα+/ERβ+) stimulated with E2 or ERα (PPT) and β (DPN)agonists were used. PTEN, Akt, p85α of PI3K, D1 cyclin and CDK4expression was determined by western blot, the subcellular localizationwas visualized using confocal microscopy, the cell cycleprogression was analyzed by flow cytometry and the cellular proliferationwas quantified by BrdU technique. Statistical analysis: ANOVA-Tukey.During the hyperplastic/adenomatous process development thePTEN protein expression showed cytoplasmatic distribution withsignificant reduction in its levels: at 20 days of tumoral developmenta reduction of approximately 50% was observed, being almost undetectableat 60 days. Akt, p85α and cell cycle regulator proteinsD1 cyclin and CD4 significantly increased in relation with tumoraldevelopment, in agreement with the rise of proliferative phase cellnumber (S+G2/M). In GH3 ERα+/ERβ-, PTEN was found mainly inthe peripheral cytoplasm with Akt phosphorylation and cellular proliferationincrease. In contrast, in GH3 ERα+/ERβ+ cells a nuclearPTEN signal was found, reinforced with DPN stimulation, with decreasedof mitogenic activity.These observations suggest that ERα and β induce opposite effectson PTEN/PI3K/Akt signaling. Both ER stimulate PTEN importor export to and from the nucleus, activating or inhibiting PTEN/PI3K/Akt signaling regulating tumoral pituitary cell growth.Keywords: PTEN, estrogen receptors, pituitary tumor, proliferation