Abstract
The ten-eleven translocation (TET) family of methylcytosine dioxygenases initiates demethylation of DNA and is associated with tumorigenesis in many cancers; however, the mechanism is mostly unknown. Here we identify upstream activators and downstream effectors of TET1 in breast cancer using human breast cancer cells and a genetically engineered mouse model. We show that depleting the architectural transcription factor high mobility group AT-hook 2 (HMGA2) induces TET1. TET1 binds and demethylates its own promoter and the promoter of homeobox A (HOXA) genes, enhancing its own expression and stimulating expression of HOXA genes including HOXA7 and HOXA9. Both TET1 and HOXA9 suppress breast tumor growth and metastasis in mouse xenografts. The genes comprising the HMGA2-TET1-HOXA9 pathway are coordinately regulated in breast cancer and together encompass a prognostic signature for patient survival. These results implicate the HMGA2-TET1-HOX signaling pathway in the epigenetic regulation of human breast cancer and highlight the importance of targeting methylation in specific subpopulations as a potential therapeutic strategy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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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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Cell Line, Tumor
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Female
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Gene Expression Profiling
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HMGA2 Protein / genetics*
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HMGA2 Protein / metabolism
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Homeodomain Proteins / genetics*
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Homeodomain Proteins / metabolism
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Humans
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Immunoblotting
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Kaplan-Meier Estimate
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Male
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Mammary Neoplasms, Experimental / genetics
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Mammary Neoplasms, Experimental / metabolism
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Mammary Neoplasms, Experimental / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Mixed Function Oxygenases
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Neoplasm Metastasis
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Oligonucleotide Array Sequence Analysis
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Prognosis
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / genetics*
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Transplantation, Heterologous
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Wnt1 Protein / genetics
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Wnt1 Protein / metabolism
Substances
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DNA-Binding Proteins
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HMGA2 Protein
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Homeodomain Proteins
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Proto-Oncogene Proteins
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Wnt1 Protein
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homeobox protein HOXA9
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Mixed Function Oxygenases
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TET1 protein, human