title: Glucocorticoid alternative effects on proliferating and differentiated mammary epithelium are associated to opposite regulation of cell-cycle inhibitor expression.
abstract: Glucocorticoids influence post-natal mammary gland development by sequentially controlling cell proliferation, differentiation, and apoptosis. In the mammary gland, it has been demonstrated that glucocorticoid treatment inhibits epithelial apoptosis in post-lactating glands. In this study, our first goal was to identify new glucocorticoid target genes that could be involved in generating this effect. Expression profiling, by microarray analysis, revealed that expression of several cell-cycle control genes was altered by dexamethasone (DEX) treatment after lactation. Importantly, it was determined that not only the exogenous synthetic hormone, but also the endogenous glucocorticoids regulated the expression of these genes. Particularly, we found that the expression of cell cycle inhibitors p21CIP1, p18INK4c, and Atm was differentially regulated by glucocorticoids through the successive stages of mammary gland development. In undifferentiated cells, DEX treatment induced their expression and reduced cell proliferation, while in differentiated cells this hormone repressed expression of those cell cycle inhibitors and promoted survival. Therefore, differentiation status determined the effect of glucocorticoids on mammary cell fate. Particularly, we have determined that p21CIP1 inhibition would mediate the activity of these hormones in differentiated mammary cells because over-expression of this protein blocked DEX-induced apoptosis protection. Together, our data suggest that the multiple roles played by glucocorticoids in mammary gland development and function might be at least partially due to the alternative roles that these hormones play on the expression of cell cycle regulators.
authors.affiliation: IFIBYNE-CONICET, Buenos Aires, Argentina.
authors.forename: Esteban
authors.initials: E
authors.lastname: Hoijman
authors.forename: Luciana
authors.initials: L
authors.lastname: Rocha-Viegas
authors.forename: Susana G
authors.initials: SG
authors.lastname: Kalko
authors.forename: Natalia
authors.initials: N
authors.lastname: Rubinstein
authors.forename: Manuel
authors.initials: M
authors.lastname: Morales-Ruiz
authors.forename: Elisa Bal de Kier
authors.initials: EB
authors.lastname: Joffé
authors.forename: Edith C
authors.initials: EC
authors.lastname: Kordon
authors.forename: Adali
authors.initials: A
authors.lastname: Pecci
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D007774:Lactation / Q000187:drug effects / Q000235:genetics; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: C493957:Cdkn1a protein, mouse; C493972:Cdkn2c protein, mouse; D018797:Cell Cycle Proteins; D050763:Cyclin-Dependent Kinase Inhibitor p18; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D025521:Tumor Suppressor Proteins; D003907:Dexamethasone; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases