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

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.

Pubmed ID: 16120603


  • Grimm SL
  • Contreras A
  • Barcellos-Hoff MH
  • Rosen JM


The Journal of biological chemistry

Publication Data

October 28, 2005

Associated Grants

  • Agency: NCI NIH HHS, Id: CA16303

Mesh Terms

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