CEBP factors regulate telomerase reverse transcriptase promoter activity in whey acidic protein‐T mice during mammary carcinogenesis. Issue 9 (25th October 2012)

• Record Type: Journal Article
• Authors: Kumar, Mukesh; Witt, Britta; Knippschild, Uwe; Koch, Sylvia; Meena, Jitendra K.; Heinlein, Christina; Weise, Julia M.; Krepulat, Frauke; Kuchenbauer, Florian; Iben, Sebastian; Rudolph, Karl‐Lenhard; Deppert, Wolfgang; Günes, Cagatay
• Is Part Of: International journal of cancer. Volume 132:Issue 9(2013:May 01)
• Page Start: 2032
• Page End: 2043
• Publication Date: 2012-10-25
• Subjects: Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.27880
• Languages: English
• ISSNs: 0020-7136

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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 (<italic>TERT</italic>) gene expression <italic>in vivo</italic> (<italic>hTERT</italic>p‐<italic>lacZ</italic>). In the present study, <italic>hTERT</italic>p‐<italic>lacZ</italic>xWAP‐<italic>T</italic> bitransgenic mice were generated to analyze the mechanisms responsible for human and mouse <italic>TERT</italic> upregulation during tumor progression <italic>in vivo</italic>. We found that telomerase activity and <italic>TERT</italic> expression were consistently upregulated in SV40‐induced invasive mammary tumors compared to normal and hyperplastic tissues and ductal carcinoma <italic>in situ</italic> (DCIS). Human and mouse <italic>TERT</italic> genes are regulated similarly in the breast tissue, involving the <italic>CEBP</italic> transcription factors. Loss of <italic>CEBP</italic>‐α and induction of <italic>CEBP</italic>‐β expression correlated well with the activation of <italic>TERT</italic> expression in mouse mammary tumors. Transfection of <italic>CEBP</italic>‐α into human or murine cells resulted in <italic>TERT</italic> repression, whereas knockdown of <italic>CEBP</italic>‐α in primary human mammary epithelial cells resulted in reactivation of endogenous <italic>TERT</italic> expression and telomerase activity. Conversely, ectopic expression of <italic>CEBP</italic>‐β activated endogenous <italic>TERT</italic> gene expression. Moreover, ChIP and EMSA experiments revealed binding of <italic>CEBP</italic>‐α and <italic>CEBP</italic>‐β to human <italic>TERT‐</italic>promoter. This is the first evidence indicating that <italic>CEBP</italic>‐α and <italic>CEBP</italic>‐β are involved in <italic>TERT</italic> gene regulation during carcinogenesis.</p> </abstract>