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Ets regulation of the erbB2 promoter

Oncogene volume 19, pages 6490–6502 (2000)Cite this article

Abstract

Evaluating the chromatinized erbB2 gene in nuclei from breast cancer cells expressing varying levels of ErbB2 transcripts, we identified a nuclease-sensitive site within a 0.22 kb region of maximum enhancer activity centered over a conserved 28 bp polypurine(GGA)-polypyrimidine(TCC) mirror-repeat and an adjacent essential Ets binding site (EBS). Promoter footprinting with nuclear extracts reveals an intense Ets hypersensitivity site at the EBS whose degree of intensity correlates with the level of cellular ErbB2 expression. In vitro mapping assays show that the supercoiled erbB2 promoter forms an internal triplex structure (Hr-DNA) at the mirror-repeat element. Mutations preventing Hr-DNA formation can enhance erbB2 promoter activity in human breast cancer cells, a result consistent with previous demonstration that Ets-erbB2 promoter complexes cannot form when the mirror-repeat is engaged in triplex binding, and new results suggesting that Ets binding induces severe promoter bending that may restrict local triplex formation. In addition to previously described erbB2-regulating breast cancer Ets factors (PEA3, ESX/Elf-3), Elf-1 is now shown to be another endogenously expressed Ets candidate capable of binding to and upregulating the erbB2 promoter. Given current strategies to transcriptionally inhibit ErbB2 overexpression, including development of novel erbB2 promoter-targeted therapeutics, an EBS-targeted approach is presented using chimeric Ets proteins that strongly repress erbB2 promoter activity.

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Acknowledgements

We are honored to dedicate this article to Takis S Papas, whose prodigious efforts and insights were key to unmasking an obscure virally transduced avian oncogene (E26) as the prototype for the multigene family of Ets transcription factors. The current research was supported by NIH sponsored RO1-CA36773, PO1-CA44768 and P50-CA58207 grants, as well as the Hazel P Munroe and Janet Landfear (Mt. Zion Health Systems) memorial funds. We thank Xiaohui Xiong, Susan Edgerton, Karen Chew, and Britt-Marie Ljung for their project assistance and Sarah Noonberg for her early contributions. C Chang was a Landfear's Fellow; and K Erny was supported by a Swiss Cancer League Grant, BIL SKL 295-2-1996.

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Authors and Affiliations

  1. Division of Oncology-Hematology, Department of Medicine, University of California at San Francisco, San Francisco, CA 94143, California, USA

    Gary K Scott, Chuan-H Chang, Katrina M Erny, Fan Xu & Christopher C Benz

  2. Molecular Genetics Program and Cancer Center, Wistar Institute, Philadelphia, PA 19104, Pennsylvania, USA

    William J Fredericks & Frank J Rauscher III

  3. Department of Pathology, Evanston Hospital/Northwestern University, Evanston, IL 60201, Illinois, USA

    Ann D Thor

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Scott, G., Chang, CH., Erny, K. et al. Ets regulation of the erbB2 promoter. Oncogene 19, 6490–6502 (2000). https://doi.org/10.1038/sj.onc.1204041

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