C/EBPbeta, but not C/EBPalpha, is essential for ductal morphogenesis, lobuloalveolar proliferation, and functional differentiation in the mouse mammary gland

Genes Dev. 1998 Jun 15;12(12):1917-28. doi: 10.1101/gad.12.12.1917.


The CCAAT/enhancer binding proteins (C/EBPs) are differentially expressed throughout mammary gland development and interact with binding sites within the promoter of a milk protein gene, beta-casein. The specific roles of C/EBPbeta and C/EBPalpha in mouse mammary gland development and differentiation have been investigated in mice that carry targeted deletions of these genes. C/EBPbeta-/- virgin mice exhibited cystic, enlarged mammary ducts with decreased secondary branching. Transplantation of C/EBPbeta-/- mammary epithelium into the cleared mammary fat pads of nude mice confirmed that this defect in ductal morphogenesis was intrinsic to the epithelium. When treated with estrogen/progesterone (E+P) to simulate pregnancy, C/EBPbeta-/- mammary glands displayed only limited lobuloalveolar development and ductal side branching. Primary mammary epithelial cells obtained from E+P-treated C/EBPbeta-/- mice that were cultured on extracellular matrix gels did not functionally differentiate in response to lactogenic hormones despite their organization into three-dimensional structures. Expression of beta-casein protein was inhibited 85%-100% and whey acidic protein (WAP) was undetectable. In contrast, no detectable alterations in mammary development or beta-casein expression were observed in mammary outgrowths derived from newborn C/EBPalpha-/- mammary epithelium transplanted into the cleared mammary fat pads of syngeneic hosts. These results demonstrate that C/EBPbeta, but not C/EBPalpha, is required for ductal morphogenesis, lobuloalveolar development, and functional differentiation of mammary epithelial cells.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology
  • Blotting, Northern
  • CCAAT-Enhancer-Binding Proteins
  • Caseins / antagonists & inhibitors
  • Caseins / genetics
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Cell Division / genetics
  • Cell Division / physiology
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / physiology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelium / metabolism
  • Estrogens / pharmacology
  • Female
  • Gene Deletion
  • Gene Expression / genetics
  • Male
  • Mammary Glands, Animal / drug effects
  • Mammary Glands, Animal / growth & development*
  • Mammary Glands, Animal / transplantation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Mice, Mutant Strains
  • Milk Proteins / antagonists & inhibitors
  • Milk Proteins / metabolism
  • Morphogenesis / drug effects
  • Morphogenesis / physiology
  • Mutation / genetics
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / physiology
  • Pregnancy
  • Progesterone / pharmacology
  • RNA, Messenger / analysis
  • Tissue Transplantation
  • Transcription Factors / genetics
  • Transcription Factors / physiology


  • CCAAT-Enhancer-Binding Proteins
  • Caseins
  • DNA-Binding Proteins
  • Estrogens
  • Milk Proteins
  • Nuclear Proteins
  • RNA, Messenger
  • Transcription Factors
  • whey acidic proteins
  • Progesterone