Cell Cycle Defects Contribute to a Block in Hormone-induced Mammary Gland Proliferation in CCAAT/Enhancer-binding Protein (C/EBPβ)-null Mice

• Published in: The Journal of biological chemistry Vol. 280; no. 43; pp. 36301 - 36309
• Main Authors: Grimm, Sandra L., Contreras, Alejandro, Barcellos-Hoff, Mary-Helen, Rosen, Jeffrey M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.10.2005; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Blotting, Western; CCAAT-Enhancer-Binding Protein-beta - genetics; CCAAT-Enhancer-Binding Protein-beta - metabolism; cdc25 Phosphatases - 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
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M508167200

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/EBPβ)-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/EBPβ-null mammary epithelial cells (MECs). These studies indicated that cell cycle progression in C/EBPβ-null MECs is blocked at the G1/S transition. C/EBPβ-null mammary glands display substantially increased levels of the activated form of transforming growth factor β, 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/EBPβ-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/EBPβ-null mammary epithelial cells from responding to hormone-induced proliferative signals.