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Published online 28 June 2004. doi:10.1083/jcb.200403020
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 166, Number 1, 133-143
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Article

 Organization of mammary epithelial cells into 3D acinar structures requires glucocorticoid and JNK signaling

Janice Murtagh, Emmett McArdle, Emer Gilligan, Laura Thornton, Fiona Furlong, and Finian Martin

Conway Institute of Biomolecular and Biomedical Research and Department of Pharmacology, University College Dublin, Belfield, Dublin 4, Ireland

Address correspondence to Finian Martin, Conway Institute of Biomolecular and Biomedical Research and Dept. of Pharmacology, University College Dublin, Belfield, Dublin 4, Ireland. Tel.: 353-1-716-2808. Fax: 353-1-269-2749. email: finian.martin{at}ucd.ie


Abstract
Mammary epithelial cells cultured on a concentrated laminin-rich extracellular matrix formed 3D acinar structures that matured to polarized monolayers surrounding a lumen. In the absence of glucocorticoids mature acinus formation failed and the expression of an acinus-associated, activator protein 1 (AP1) and nuclear factor {kappa}B transcription factor DNA-binding profile was lost. Treatment with the JNK inhibitor, SP600125, caused similar effects, whereas normal organization of the mammary epithelial cells as acini caused JNK activation in a glucocorticoid-dependent manner. The forming acini expressed BRCA1, GADD45ß, MEKK4, and the JNK activating complex GADD 45ß–MEKK4 in a glucocorticoid-dependent fashion. JNK catalyzed phosphorylation of c-Jun was also detected in the acini. In addition, expression of ß4 integrin and in situ occupation of its promoter by AP1 components, c-Jun and Fos, was glucocorticoid dependent. These results suggest that glucocortocoid signaling regulates acinar integrity through a pathway involving JNK regulation of AP1 transcription factors and ß4 integrin expression.

Key Words: glucocorticoid; mammary epithelial cell; acinus; JNK; BRCA1

J. Murtagh's current address is Dept. of Oncology, Montefiore Medical Center, 111 East 210th St., Bronx, NY 10467.

Abbreviations used in this paper: AP1, activator protein 1; ChIP, chromatin immunoprecipitation; EHS, Engelbreth-Holm-Swarm; EMSA, electrophoretic mobility shift analysis; EtBr, ethidium bromide; GADD45, growth arrest and DNA damage inducible; NF{kappa}B, nuclear factor {kappa}B.


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