title: CEBP factors regulate telomerase reverse transcriptase promoter activity in whey acidic protein-T mice during mammary carcinogenesis.
abstract: Telomerase is activated in the majority of invasive breast cancers, but the time point of telomerase activation during mammary carcinogenesis is not clear. We have recently presented a transgenic mouse model to study human telomerase reverse transcriptase (TERT) gene expression in vivo (hTERTp-lacZ). In the present study, hTERTp-lacZxWAP-T bitransgenic mice were generated to analyze the mechanisms responsible for human and mouse TERT upregulation during tumor progression in vivo. We found that telomerase activity and TERT expression were consistently upregulated in SV40-induced invasive mammary tumors compared to normal and hyperplastic tissues and ductal carcinoma in situ (DCIS). Human and mouse TERT genes are regulated similarly in the breast tissue, involving the CEBP transcription factors. Loss of CEBP-α and induction of CEBP-β expression correlated well with the activation of TERT expression in mouse mammary tumors. Transfection of CEBP-α into human or murine cells resulted in TERT repression, whereas knockdown of CEBP-α in primary human mammary epithelial cells resulted in reactivation of endogenous TERT expression and telomerase activity. Conversely, ectopic expression of CEBP-β activated endogenous TERT gene expression. Moreover, ChIP and EMSA experiments revealed binding of CEBP-α and CEBP-β to human TERT-promoter. This is the first evidence indicating that CEBP-α and CEBP-β are involved in TERT gene regulation during carcinogenesis.
authors.affiliation: Institute of Molecular Medicine and Max-Planck Research Group on Stem Cell Aging, Ulm, Germany.
authors.forename: Mukesh
authors.initials: M
authors.lastname: Kumar
authors.forename: Britta
authors.initials: B
authors.lastname: Witt
authors.forename: Uwe
authors.initials: U
authors.lastname: Knippschild
authors.forename: Sylvia
authors.initials: S
authors.lastname: Koch
authors.forename: Jitendra K
authors.initials: JK
authors.lastname: Meena
authors.forename: Christina
authors.initials: C
authors.lastname: Heinlein
authors.forename: Julia M
authors.initials: JM
authors.lastname: Weise
authors.forename: Frauke
authors.initials: F
authors.lastname: Krepulat
authors.forename: Florian
authors.initials: F
authors.lastname: Kuchenbauer
authors.forename: Sebastian
authors.initials: S
authors.lastname: Iben
authors.forename: Karl-Lenhard
authors.initials: KL
authors.lastname: Rudolph
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Deppert
authors.forename: Cagatay
authors.initials: C
authors.lastname: Günes
mesh_terms: D000818:Animals; D015153:Blotting, Western; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008156:Luciferases / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008894:Milk Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; D008894:Milk Proteins; D012333:RNA, Messenger; C024471:whey acidic proteins; D008156:Luciferases; C509186:TERT protein, human; D019098:Telomerase; C509187:Tert protein, mouse