FoxM1 regulates mammary luminal cell fate

Cell Rep. 2012 Jun 28;1(6):715-29. doi: 10.1016/j.celrep.2012.05.005. Epub 2012 Jun 7.


Elevated expression of FoxM1 in breast cancer correlates with an undifferentiated tumor phenotype and a negative clinical outcome. However, a role for FoxM1 in regulating mammary differentiation was not known. Here, we identify another function of FoxM1, the ability to act as a transcriptional repressor, which plays an important role in regulating the differentiation of luminal epithelial progenitors. Regeneration of mammary glands with elevated levels of FoxM1 leads to aberrant ductal morphology and expansion of the luminal progenitor pool. Conversely, knockdown of FoxM1 results in a shift toward the differentiated state. FoxM1 mediates these effects by repressing the key regulator of luminal differentiation, GATA-3. Through association with DNMT3b, FoxM1 promotes methylation of the GATA-3 promoter in an Rb-dependent manner. This study identifies FoxM1 as a critical regulator of mammary differentiation with significant implications for the development of aggressive breast cancers.

Publication types

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

MeSH terms

  • Animals
  • Base Sequence
  • Binding Sites
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Lineage*
  • Cell Proliferation
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA Methylation / genetics
  • DNA Methyltransferase 3B
  • Female
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors / metabolism*
  • GATA3 Transcription Factor / metabolism
  • Gene Knockdown Techniques
  • Humans
  • Mammary Glands, Animal / growth & development
  • Mammary Glands, Animal / metabolism*
  • Mammary Glands, Animal / pathology*
  • Mammary Glands, Human / growth & development
  • Mammary Glands, Human / metabolism*
  • Mammary Glands, Human / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Pregnancy
  • Promoter Regions, Genetic / genetics
  • Retinoblastoma Protein / metabolism
  • Transcription, Genetic


  • FOXM1 protein, human
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors
  • Foxm1 protein, mouse
  • GATA3 Transcription Factor
  • Retinoblastoma Protein
  • DNA (Cytosine-5-)-Methyltransferases