Glucocorticoid alternative effects on proliferating and differentiated mammary epithelium are associated to opposite regulation of cell-cycle inhibitor expression

• Published in: Journal of cellular physiology Vol. 227; no. 4; pp. 1721 - 1730
• Main Authors: Hoijman, Esteban, Rocha-Viegas, Luciana, Kalko, Susana G., Rubinstein, Natalia, Morales-Ruiz, Manuel, Joffé, Elisa Bal de Kier, Kordon, Edith C., Pecci, Adali
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.04.2012
• Subjects: Animals; Ataxia Telangiectasia Mutated Proteins; Cell Cycle - drug effects; Cell Cycle - genetics; Cell Cycle Proteins - genetics; Cell Differentiation - drug effects; Cell Proliferation - drug effects; Cyclin-Dependent Kinase Inhibitor p18 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Dexamethasone - pharmacology; DNA-Binding Proteins - genetics; Epithelial Cells - cytology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Female; Gene Expression Regulation, Developmental - drug effects; Glucocorticoids - pharmacology; Lactation - drug effects; Lactation - genetics; Mammary Glands, Animal - cytology; Mammary Glands, Animal - drug effects; Mammary Glands, Animal - growth & development; Mammary Glands, Animal - metabolism; Mice; Mice, Inbred BALB C; Protein-Serine-Threonine Kinases - genetics; Tumor Suppressor Proteins - genetics
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.22896

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. J. Cell. Physiol. 227: 1721–1730, 2012. © 2011 Wiley Periodicals, Inc.