Inhibitory role of ERβ on anterior pituitary cell proliferation by controlling the expression of proteins related to cell cycle progression.
Considering that the role of ERβ in the growth of pituitary cells is not well known, the aim of this work was to determine the expression of ERβ in normal and tumoral cells and to investigate its implications in the proliferative control of this endocrine gland, by analyzing the participation of cyclin D1, Cdk4 and p21. Our results showed that the expression of ERβ decreased during pituitary tumoral development induced by chronic E2 stimulation. The 20 ± 1.6% of normal adenohypophyseal cells expressed ERβ, with this protein being reduced in the hyperplastic/adenomatous pituitary: at 20 days the ERβ+ population was 10.7 ± 2.2%, while after 40 and 60 days of treatment an almost complete loss in the ERβ expression was observed (40 d: 1 ± 0.6%; 60 d: 2 ± 0.6%). The ERα/β ratio increased starting from tumors at 40 days, mainly due to the loss of ERβ expression. The cell proliferation was analyzed in normal and hyperplastic pituitary and also in GH3β- and GH3β+ which contained different levels of ERβ expression, and therefore different ERα/β ratios. The over-expression of ERβ inhibited the GH3 cell proliferation and expression of cyclin D1 and ERα. Also, the ERβ activation by its agonist DPN changed the subcellular localization of p21, inducing an increase in the p21 nuclear expression, where it acts as a tumoral suppressor. These results show that ERβ exerts an inhibitory role on pituitary cell proliferation, and that this effect may be partially due to the modulation of some key regulators of the cell cycle, such as cyclin D1 and p21. These data contribute significantly to the understanding of the ER effects in the proliferative control of pituitary gland, specifically related to the ERβ function in the E2 actions on this endocrine gland.
Centro de Microscopía Electrónica, Instituto de Investigaciones en Ciencias de la Salud (INICSA-CONICET), Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
Pablo A
PA
Pérez
Centro de Microscopía Electrónica, Instituto de Investigaciones en Ciencias de la Salud (INICSA-CONICET), Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
Juan P
JP
Petiti
Centro de Microscopía Electrónica, Instituto de Investigaciones en Ciencias de la Salud (INICSA-CONICET), Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
Ignacio A
IA
Wagner
Centro de Microscopía Electrónica, Instituto de Investigaciones en Ciencias de la Salud (INICSA-CONICET), Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
Maria E
ME
Sabatino
Laboratorio de Hormonas y Biología del Cáncer, Instituto de Medicina y Biología Experimental de Cuyo, (IMBECU-CONICET), CCT-Mendoza, Mendoza, Argentina.
Corina V
CV
Sasso
Centro de Microscopía Electrónica, Instituto de Investigaciones en Ciencias de la Salud (INICSA-CONICET), Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
Ana L
AL
De Paul
Centro de Microscopía Electrónica, Instituto de Investigaciones en Ciencias de la Salud (INICSA-CONICET), Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
Alicia I
AI
Torres
Centro de Microscopía Electrónica, Instituto de Investigaciones en Ciencias de la Salud (INICSA-CONICET), Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina. Electronic address: silvina@cmefcm.uncor.edu.
Silvina
S
Gutiérrez
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004958:Estradiol / Q000009:adverse effects*; D047629:Estrogen Receptor beta / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D009243:NAD / Q000494:pharmacology; D010903:Pituitary Gland, Anterior / Q000166:cytology* / Q000378:metabolism; D010911:Pituitary Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D051381:Rats
C530106:Ccnd1 protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047629:Estrogen Receptor beta; D009243:NAD; D019938:Cyclin D1; D004958:Estradiol; C495903:Cdk4 protein, rat; D051358:Cyclin-Dependent Kinase 4
Cell proliferation; Cyclin D1; Estradiol; Estrogen receptor β; Pituitary; p21