PMID:16980615

Citation	Wu, K, Li, A, Rao, M, Liu, M, Dailey, V, Yang, Y, Di Vizio, D, Wang, C, Lisanti, MP, Sauter, G, Russell, RG, Cvekl, A and Pestell, RG (2006) DACH1 is a cell fate determination factor that inhibits cyclin D1 and breast tumor growth. Mol. Cell. Biol. 26:7116-29
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 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.
Links	PubMed PMC1592900 Online version:10.1128/MCB.00268-06
Keywords	Animals; Binding Sites; Breast Neoplasms/pathology; Cells, Cultured; Cyclin D1/genetics; Cyclin D1/metabolism; DNA/biosynthesis; DNA/metabolism; Epithelial Cells/cytology; Epithelial Cells/metabolism; Epithelial Cells/pathology; Eye Proteins/metabolism; Female; Humans; Mammary Glands, Animal/growth & development; Mammary Glands, Human/growth & development; Mice; Mice, Nude; Neoplasm Invasiveness/pathology; Neoplasm Metastasis/pathology; Phenotype; Promoter Regions, Genetic/genetics; Protein Structure, Tertiary; Proto-Oncogene Proteins c-myc/metabolism; Transcription Factor AP-1/metabolism; Transcription Factors/metabolism; Tumor Stem Cell Assay; ras Proteins/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:DACH1		GO:0048147: negative regulation of fibroblast proliferation	ECO:0000315:		P		Figure 1 shows induction of DACH1 represses colony formation and tumor growth.	complete CACAO 6239
HUMAN:DACH1		GO:2000279: negative regulation of DNA biosynthetic process	ECO:0000314:		P		figure 2 shows dna synthesis inhibition through the DS domain of DACH1	complete CACAO 6243
HUMAN:DACH1	involved_in	GO:2000279: negative regulation of DNA biosynthetic process	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:DACH1		GO:0033262: regulation of DNA replication involved in S phase	ECO:0000315:		P		Inducible DACH1 expression inhibits colony formation and tumor growth in vivo.	complete CACAO 6820
MOUSE:DACH1		GO:0043433: negative regulation of sequence-specific DNA binding transcription factor activity	ECO:0000315:		P		Figure 5D shows the cyclin D1 promoter was repressed in a dose-dependent manner by the expression of DACH1, and deletion of the DACH1 DS domain abrogated repression of the cyclin D1 promoter.	complete CACAO 6972
MOUSE:DACH1	involved_in	GO:0033262: regulation of nuclear cell cycle DNA replication	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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