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ZNF217, a candidate breast cancer oncogene amplified at 20q13, regulates expression of the ErbB3 receptor tyrosine kinase in breast cancer cells

Oncogene volume 29, pages 5500–5510 (2010)Cite this article

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Abstract

Understanding the mechanisms underlying ErbB3 overexpression in breast cancer will facilitate the rational design of therapies to disrupt ErbB2-ErbB3 oncogenic function. Although ErbB3 overexpression is frequently observed in breast cancer, the factors mediating its aberrant expression are poorly understood. In particular, the ErbB3 gene is not significantly amplified, raising the question as to how ErbB3 overexpression is achieved. In this study we showed that the ZNF217 transcription factor, amplified at 20q13 in ∼20% of breast tumors, regulates ErbB3 expression. Analysis of a panel of human breast cancer cell lines (n=50) and primary human breast tumors (n=15) showed a strong positive correlation between ZNF217 and ErbB3 expression. Ectopic expression of ZNF217 in human mammary epithelial cells induced ErbB3 expression, whereas ZNF217 silencing in breast cancer cells resulted in decreased ErbB3 expression. Although ZNF217 has previously been linked with transcriptional repression because of its close association with C-terminal-binding protein (CtBP)1/2 repressor complexes, our results show that ZNF217 also activates gene expression. We showed that ZNF217 recruitment to the ErbB3 promoter is CtBP1/2-independent and that ZNF217 and CtBP1/2 have opposite roles in regulating ErbB3 expression. In addition, we identify ErbB3 as one of the mechanisms by which ZNF217 augments PI-3K/Akt signaling.

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Acknowledgements

This work was supported by NIH grant R01 CA118384 (CS); NIH grant RO1 CA45250 (PJF); U54 CA112970 (PY, RN), and the Office of Energy Research, Office of Health and Biological Research, US Department of Energy under Contract No. DE-AC03-76SF00098 (PY) and NIH Center for Research Resources (NCRR) UL1 RR024146 (LAB). JM was a recipient of a DOD Breast Cancer Research Program Predoctoral fellowship: W81XWH-06-1-0402. We thank Dr Nelly Auersperg (U Vancouver) for the recombinant adenoviral ZNF217 construct and Jeremy Semeiks for his assistance with the adenoviral transduction experiments. We thank Dr Jeffrey Hildebrand for the CtBP2-null mef-90 fibroblasts and Dr Merlin Crossly for the CtBP2_pcDNA_3.1 expression construct. We thank Dr Hongwu Chen for the pCmX vector, Dr James Trimmer for the co-REST ascites and Dr Martha Stampfer for the HMEC 184 cells. CTCS statistical support is made possible by Grant Number UL1 RR024146 from the Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. A special thank you to members of the Farnham lab for valuable discussions.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Medicine, Divison of Basic Sciences, University of California at Davis Cancer Center, Sacramento, CA, USA

    S R Krig, J K Miller & C A Sweeney

  2. Department of Public Health Sciences, Division of Biostatistics, University of California, Davis, CA, USA

    S Frietze & P J Farnham

  3. Genentech Inc., San Francisco, CA, USA

    L A Beckett

  4. Department of Pharmacology, The Genome Center, University of California, Davis, CA, USA

    R M Neve

  5. Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA

    P I Yaswen

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Krig, S., Miller, J., Frietze, S. et al. ZNF217, a candidate breast cancer oncogene amplified at 20q13, regulates expression of the ErbB3 receptor tyrosine kinase in breast cancer cells. Oncogene 29, 5500–5510 (2010). https://doi.org/10.1038/onc.2010.289

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