HER2/Neu tumorigenesis and metastasis is regulated by E2F activator transcription factors

Oncogene. 2015 Jan 8;34(2):217-25. doi: 10.1038/onc.2013.540. Epub 2013 Dec 23.


HER2/Neu is amplified and overexpressed in a large proportion of human breast cancers, but the signaling pathways that contribute to tumor development and metastatic progression are not completely understood. Using gene expression data and pathway signatures, we predicted a role for activator E2F transcription factors in Neu-induced tumors. This was genetically tested by interbreeding Neu transgenics with knockouts of the three activator E2Fs. Loss of any E2F delayed Neu-induced tumor onset. E2F1 loss accelerated tumor growth, while E2F2 and E2F3 loss did not. Strikingly, it was observed that loss of E2F1 or E2F2 significantly reduced the metastatic capacity of the tumor and this was associated with a reduction in circulating tumor cells in the E2F2 knockout. Gene expression analysis between the tumors in the various E2F-mutant backgrounds revealed that there was extensive compensation by other E2F family members in the individual knockouts, underscoring the importance of the E2Fs in HER2/Neu-induced tumors. Extension to HER2-positive (HER2+) human breast cancer revealed a number of HER2+ subtypes based on E2F activity with differences in relapse-free survival times. Taken together, these data demonstrate that the E2F transcription factors are integral to HER2+ tumor development and progression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Carcinogenesis
  • Disease Models, Animal
  • E2F Transcription Factors / deficiency
  • E2F Transcription Factors / genetics
  • E2F Transcription Factors / metabolism*
  • Female
  • Humans
  • Mammary Neoplasms, Experimental / enzymology
  • Mammary Neoplasms, Experimental / metabolism*
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mice, Knockout
  • Mice, Nude
  • Neoplasm Metastasis
  • Neoplastic Cells, Circulating / pathology
  • Receptor, ErbB-2 / metabolism*
  • Signal Transduction


  • E2F Transcription Factors
  • ERBB2 protein, human
  • Erbb2 protein, mouse
  • Receptor, ErbB-2