DACH1 is a cell fate determination factor that inhibits cyclin D1 and breast tumor growth.
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 alpha-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.
Wu
Kongming
K
Kimmel Cancer Center, Department of Cancer Biology, Bluemle Life Sciences Building, Philadelphia, Pennsylvania 19107, USA.
Li
Anping
A
Rao
Mahadev
M
Liu
Manran
M
Dailey
Vernon
V
Yang
Ying
Y
Di Vizio
Dolores
D
Wang
Chenguang
C
Lisanti
Michael P
MP
Sauter
Guido
G
Russell
Robert G
RG
Cvekl
Ales
A
Pestell
Richard G
RG
D000818:Animals; D001665:Binding Sites; D001943:Breast Neoplasms / Q000473:pathology*; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D005136:Eye Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D008321:Mammary Glands, Animal / Q000254:growth & development; D042361:Mammary Glands, Human / Q000254:growth & development; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D009362:Neoplasm Metastasis / Q000473:pathology; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D017434:Protein Structure, Tertiary; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014410:Tumor Stem Cell Assay; D018631:ras Proteins / Q000378:metabolism
C486747:DACH1 protein, human; C456264:Dach1 protein, mouse; D005136:Eye Proteins; D016271:Proto-Oncogene Proteins c-myc; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D019938:Cyclin D1; D004247:DNA; D018631:ras Proteins