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

J Cell Biol. 2004 Jul 5;166(1):133-43. doi: 10.1083/jcb.200403020. Epub 2004 Jun 28.

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 kappaB 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, GADD45beta, MEKK4, and the JNK activating complex GADD 45beta-MEKK4 in a glucocorticoid-dependent fashion. JNK catalyzed phosphorylation of c-Jun was also detected in the acini. In addition, expression of beta4 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 beta4 integrin expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anthracenes / pharmacology
  • BRCA1 Protein / metabolism
  • Blotting, Western
  • Cell Culture Techniques / methods
  • Cells, Cultured
  • Chromatin / metabolism
  • Epithelial Cells / cytology*
  • Extracellular Matrix / metabolism
  • Glucocorticoids / metabolism*
  • Integrin beta4 / metabolism
  • Integrins / metabolism
  • JNK Mitogen-Activated Protein Kinases*
  • Lactation
  • Luciferases / metabolism
  • MAP Kinase Kinase 4
  • Mammary Glands, Animal / cytology*
  • Mice
  • Microscopy, Fluorescence
  • Mitogen-Activated Protein Kinase Kinases / metabolism*
  • Models, Biological
  • Phosphorylation
  • Precipitin Tests
  • Proto-Oncogene Proteins c-fos / metabolism
  • Proto-Oncogene Proteins c-jun / metabolism
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Time Factors
  • Transcription Factor AP-1 / metabolism
  • Transfection

Substances

  • Anthracenes
  • BRCA1 Protein
  • Chromatin
  • Glucocorticoids
  • Integrin beta4
  • Integrins
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • RNA, Messenger
  • Transcription Factor AP-1
  • pyrazolanthrone
  • Luciferases
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases