Estrogen receptor β regulates the tumoral suppressor PTEN to modulate pituitary cell growth

• Published in: Journal of cellular physiology Vol. 233; no. 2; pp. 1402 - 1413
• Main Authors: Perez, Pablo A., Petiti, Juan P., Picech, Florencia, Guido, Carolina B., dV Sosa, Liliana, Grondona, Ezequiel, Mukdsi, Jorge H., De Paul, Ana L., Torres, Alicia I., Gutierrez, Silvina
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.02.2018
• Subjects: Animals; Cell cycle; Cell growth; Cell Proliferation; Cells, Cultured; Chromosome 10; Estradiol - metabolism; Estradiol - pharmacology; Estrogen Receptor beta - agonists; Estrogen Receptor beta - genetics; Estrogen Receptor beta - metabolism; estrogen receptor β; Estrogen receptors; Estrogen Replacement Therapy; Estrogens; Estrous Cycle - metabolism; Estrus cycle; Female; G1 Phase; Glands; Homology; Immunofluorescence; lactotroph; Lactotrophs - drug effects; Lactotrophs - enzymology; Localization; Male; Nitriles - pharmacology; Nuclei; Ovariectomy; Overexpression; Phosphatase; pituitary; Pituitary (anterior); Proteins; PTEN; PTEN Phosphohydrolase - metabolism; PTEN protein; Rats; Rats, Wistar; Rodents; Signal Transduction; Signaling; somatotroph; Somatotrophs - drug effects; Somatotrophs - enzymology; Tensin; Transfection; Xenoestrogens; pituitary; somatotroph; PTEN; lactotroph; estrogen receptor β
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.26025

In this study, we focused on ERβ regulation in the adenohypophysis under different estrogenic milieu, by analyzing whether ER modulates the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression and its subcellular localization on anterior pituitary glands from Wistar rats and GH3 lactosomatotroph cells that over‐expressed ERβ. ERβ was regulated in a cyclic manner, and underwent dynamic changes throughout the estrous cycle, with decreased ERβ+ cells in estrus and under E2 treatment, but increased in ovariectomized rats. In addition, the ERα/β ratio increased in estrus and under E2 stimulation, but decreased in ovariectomized rats. Double immunofluorescence revealed that lactotroph and somatotroph ERβ+ were significantly decreased in estrus. Also, variations in the PTEN expression was observed, which was diminished with high E2 conditions but augmented with low E2 milieu. The subcellular localization of this phosphatase was cell cycle‐dependent, with remarkable changes in the immunostaining pattern: nuclear in arrested pituitary cells but cytoplasmic in stimulated cells, and responding differently to ER agonists, with only DPN being able to increase PTEN expression and retaining it in the nucleus. Finally, ERβ over‐expression increased PTEN with a noticeable subcellular redistribution, and with a significant nuclear signal increase in correlation with an increase of cells in G0/G1 phase. These results showed that E2 is able to inhibit ERβ expression and suggests that the tumoral suppressor PTEN might be one of the signaling proteins by which E2, through ERβ, acts to modulate pituitary cell proliferation, thereby adapting endocrine populations in relation with hormonal necessities. Pituitary ERβ and PTEN were regulated in a cyclic manner throughout the rat estrous cycle, diminished with high E2 conditions but augmented with low E2 milieu. The ERβ agonist, DPN, was able to increase pituitary PTEN expression and retaining it in the nucleus. ERβ over‐expression increased PTEN in correlation with an increment of GH3 cells in G0/G1 phase.