DACH1 is a cell fate determination factor that inhibits cyclin D1 and breast tumor growth

Kongming Wu, Anping Li, Mahadev Rao, Manran Liu, Vernon Dailey, Ying Yang, Dolores Di Vizio, Chenguang Wang, Michael P. Lisanti, Guido Sauter, Robert G. Russell, Ales Cvekl, Richard G. Pestell

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87 Citations (Scopus)

Abstract

Obstacles to the expansion of cells with proliferative potential include the induction of cell death, telomere-based senescence, and the pRb and p53 tumor suppressors. Not infrequently, the molecular pathways regulating oncogenesis recapitulate aberrations of processes governing embryogenesis. The genetic network, consisting of the dachshund (dac), eyes absent (eya), eyeless, and sine oculis (so) genes, regulates cell fate determination in metazoans, with dac serving as a cointegrator through a So DNA-binding factor. Here, DACH1 inhibited oncogene-mediated breast oncogenesis, blocking breast cancer epithelial cell DNA synthesis, colony formation, growth in Matrigel, and tumor growth in mice. Genetic deletion studies demonstrated a requirement for cyclin D1 in DACH1-mediated inhibition of DNA synthesis. DACH1 repressed cyclin D1 through a novel mechanism via a c-Jun DNA-binding partner, requiring the DACH1 α-helical DS domain which recruits corepressors to the local chromatin. Analysis of over 2,000 patients demonstrated increased nuclear DACH1 expression correlated inversely with cellular mitosis and predicted improved breast cancer patient survival. The cell fate determination factor, DACH1, arrests breast tumor proliferation and growth in vivo providing a new mechanistic and potential therapeutic insight into this common disease.

Original languageEnglish
Pages (from-to)7116-7129
Number of pages14
JournalMolecular and Cellular Biology
Volume26
Issue number19
DOIs
Publication statusPublished - 10-2006

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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    Wu, K., Li, A., Rao, M., Liu, M., Dailey, V., Yang, Y., Di Vizio, D., Wang, C., Lisanti, M. P., Sauter, G., Russell, R. G., Cvekl, A., & Pestell, R. G. (2006). DACH1 is a cell fate determination factor that inhibits cyclin D1 and breast tumor growth. Molecular and Cellular Biology, 26(19), 7116-7129. https://doi.org/10.1128/MCB.00268-06