Cell cycle defects contribute to a block in hormone-induced mammary gland proliferation in CCAAT/enhancer-binding protein (C/EBPbeta)-null mice

J Biol Chem. 2005 Oct 28;280(43):36301-9. doi: 10.1074/jbc.M508167200. Epub 2005 Aug 24.


In contrast to hormone-dependent breast cancer, steroid hormone-induced proliferation in the normal mammary gland does not occur in the steroid-receptor positive cells but rather in adjacent cells via paracrine signaling involving several local growth factors. To help elucidate the mechanisms involved in the block in proliferation in hormone-receptor positive cells, we have utilized a CCAAT/enhancer binding protein (C/EBPbeta)-null mouse model. Loss of this transcription factor results in increased steroid and prolactin receptor expression concomitant with a 10-fold decrease in proliferation in response to pregnancy hormones. To determine the basis for this decrease, several markers of cell cycle progression were analyzed in wild type and C/EBPbeta-null mammary epithelial cells (MECs). These studies indicated that cell cycle progression in C/EBPbeta-null MECs is blocked at the G1/S transition. C/EBPbeta-null mammary glands display substantially increased levels of the activated form of transforming growth factor beta, a potent inhibitor of epithelial cell proliferation, as well as increased downstream Smad2 expression and signaling. While cyclin D1 levels were equivalent, cyclin E expression was markedly reduced in C/EBPbeta-null as compared with wildtype MECs. In addition, increased p27 stability and retention in the nucleus and decreased levels of the cdc25a phosphatase contributed to a significant loss of cdk2 kinase activity. Collectively, these changes prevent C/EBPbeta-null mammary epithelial cells from responding to hormone-induced proliferative signals.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blotting, Western
  • CCAAT-Enhancer-Binding Protein-beta / genetics*
  • CCAAT-Enhancer-Binding Protein-beta / metabolism
  • Cell Cycle
  • Cell Proliferation
  • Cyclin D1 / metabolism
  • Cyclin E / metabolism
  • Epithelial Cells / cytology
  • Female
  • Histones / metabolism
  • Hormones / metabolism
  • Immunohistochemistry
  • Immunoprecipitation
  • Ki-67 Antigen / biosynthesis
  • Mammary Glands, Animal / metabolism*
  • Mammary Glands, Animal / pathology
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Transforming Growth Factor beta / metabolism
  • cdc25 Phosphatases / metabolism


  • CCAAT-Enhancer-Binding Protein-beta
  • Cyclin E
  • Histones
  • Hormones
  • Ki-67 Antigen
  • Transforming Growth Factor beta
  • Cyclin D1
  • Cdc25a protein, mouse
  • cdc25 Phosphatases