A "Yin Yang" relationship between Estrogen Receptor Alfa and Beta 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

SAIC, SAIB, SAI, SAA, SAB, SAFE, SAFIS, SAH, SAP

Previously it was shown that estrogen receptor (ER) β increased the tumoral suppressor PTEN expression to modify the lactotroph and somatotrophs population growth and adequately respond to cyclic PRL y GH requirement during the estrous cycle. Expanding these investigations, the aim of this work was to analyze the ERα and β effects on PTEN/PI3K/Akt in the pituitary tumoral growth regulation mechanisms.To carry out this objective, female rats treated with estradiol benzoate during 20, 40 and 60 days (hyperplasic/adenomatous pituitary model) and transfected GH3 tumoral cells (GH3 ERα+/ERβ- and GH3 ERα+/ERβ+) stimulated with E2 or ERα (PPT) and β (DPN) agonists were used. PTEN, Akt, p85α of PI3K, D1 cyclin and CDK4 expression was determined by western blot, the subcellular localization was visualized using confocal microscopy, the cell cycle progression was analyzed by flow cytometry and the cellular proliferation was quantified by BrdU technique. Statistical analysis: ANOVA-Tukey. During the hyperplastic/adenomatous process development the PTEN protein expression showed cytoplasmatic distribution with significant reduction in its levels: at 20 days of tumoral development a reduction of approximately 50% was observed, being almost undetectable at 60 days. Akt, p85α and cell cycle regulator proteins D1 cyclin and CD4 significantly increased in relation with tumoral development, in agreement with the rise of proliferative phase cell number (S+G2/M). In GH3 ERα+/ERβ-, PTEN was found mainly in the peripheral cytoplasm with Akt phosphorylation and cellular proliferation increase. In contrast, in GH3 ERα+/ERβ+ cells a nuclear PTEN signal was found, reinforced with DPN stimulation, with decreased of mitogenic activity. These observations suggest that ERα and β induce opposite effects on PTEN/PI3K/Akt signaling. Both ER stimulate PTEN import or export to and from the nucleus, activating or inhibiting PTEN/PI3K/Akt signaling regulating tumoral pituitary cell growth.