Abstract
The cell fate determination factor Dachshund was cloned as a dominant inhibitor of the hyperactive epidermal growth factor receptor ellipse. The expression of Dachshund is lost in human breast cancer associated with poor prognosis. Breast tumor-initiating cells (TIC) may contribute to tumor progression and therapy resistance. Here, endogenous DACH1 was reduced in breast cancer cell lines with high expression of TIC markers and in patient samples of the basal breast cancer phenotype. Re-expression of DACH1 reduced new tumor formation in serial transplantations in vivo, reduced mammosphere formation, and reduced the proportion of CD44(high)/CD24(low) breast tumor cells. Conversely, lentiviral shRNA to DACH1 increased the breast (B)TIC population. Genome-wide expression studies of mammary tumors demonstrated DACH1 repressed a molecular signature associated with stem cells (SOX2, Nanog, and KLF4) and genome-wide ChIP-seq analysis identified DACH1 binding to the promoter of the Nanog, KLF4, and Lin28 genes. KLF4/c-Myc and Oct4/Sox2 antagonized DACH1 repression of BTIC. Mechanistic studies demonstrated DACH1 directly repressed the Nanog and Sox2 promoters via a conserved domain. Endogenous DACH1 regulates BTIC in vitro and in vivo.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ARNTL Transcription Factors / genetics
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ARNTL Transcription Factors / metabolism*
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Animals
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism*
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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CD24 Antigen / genetics
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CD24 Antigen / metabolism
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Cell Dedifferentiation*
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Cell Line, Tumor
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Eye Proteins / genetics
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Eye Proteins / metabolism*
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Female
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Genome-Wide Association Study
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Hyaluronan Receptors / genetics
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Hyaluronan Receptors / metabolism
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Kruppel-Like Factor 4
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Kruppel-Like Transcription Factors / genetics
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Kruppel-Like Transcription Factors / metabolism
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Mice
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Mice, Nude
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Nanog Homeobox Protein
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Neoplasm Transplantation
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Neoplastic Stem Cells / metabolism*
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Neoplastic Stem Cells / pathology
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Octamer Transcription Factor-3 / genetics
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Octamer Transcription Factor-3 / metabolism
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Promoter Regions, Genetic / genetics
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism
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SOXB1 Transcription Factors / genetics
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SOXB1 Transcription Factors / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism*
Substances
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ARNTL Transcription Factors
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BMAL1 protein, human
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Biomarkers, Tumor
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CD24 Antigen
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CD24 protein, human
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CD44 protein, human
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DACH1 protein, human
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Eye Proteins
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Homeodomain Proteins
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Hyaluronan Receptors
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KLF4 protein, human
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Klf4 protein, mouse
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Kruppel-Like Factor 4
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Kruppel-Like Transcription Factors
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Lin28A protein, human
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MYC protein, human
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NANOG protein, human
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Nanog Homeobox Protein
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Octamer Transcription Factor-3
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POU5F1 protein, human
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Proto-Oncogene Proteins c-myc
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RNA-Binding Proteins
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SOX2 protein, human
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SOXB1 Transcription Factors
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Transcription Factors