title: HMGA2/TET1/HOXA9 signaling pathway regulates breast cancer growth and metastasis.
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.
authors.affiliation: Ben May Department for Cancer Research, Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Miao
authors.initials: M
authors.lastname: Sun
authors.forename: Chun-Xiao
authors.initials: CX
authors.lastname: Song
authors.forename: Hao
authors.initials: H
authors.lastname: Huang
authors.forename: Casey A
authors.initials: CA
authors.lastname: Frankenberger
authors.forename: Devipriya
authors.initials: D
authors.lastname: Sankarasharma
authors.forename: Suzana
authors.initials: S
authors.lastname: Gomes
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Jianjun
authors.initials: J
authors.lastname: Chen
authors.forename: Kiran K
authors.initials: KK
authors.lastname: Chada
authors.forename: Chuan
authors.initials: C
authors.lastname: He
authors.forename: Marsha R
authors.initials: MR
authors.lastname: Rosner
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D025743:HMGA2 Protein / Q000235:genetics* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D053208:Kaplan-Meier Estimate; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D006899:Mixed Function Oxygenases; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D014183:Transplantation, Heterologous; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D025743:HMGA2 Protein; D018398:Homeodomain Proteins; D011518:Proto-Oncogene Proteins; D051155:Wnt1 Protein; C097899:homeobox protein HOXA9; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human