The transcription factor ZNF217 Is a prognostic biomarker and therapeutic target during breast cancer progression

Laurie E. Littlepage, Adam S. Adler, Hosein Kouros-Mehr, Guiqing Huang, Jonathan Chou, Sheryl R. Krig, Obi L. Griffi th, James E. Korkola, Kun Qu, Devon A. Lawson, Qing Xue, Mark D. Sternlicht, Gerrit J P Dijkgraaf, Paul Yaswen, Hope S. Rugo, Colleen A Sweeney, Colin C. Collins, Joe W. Gray, Howard Y. Chang, Zena Werb

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

The transcription factor ZNF217 is a candidate oncogene in the amplicon on chromosome 20q13 that occurs in 20% to 30% of primary human breast cancers and that correlates with poor prognosis. We show that Znf217 overexpression drives aberrant differentiation and signaling events, promotes increased self-renewal capacity, mesenchymal marker expression, motility, and metastasis, and represses an adult tissue stem cell gene signature downregulated in cancers. By in silico screening, we identifi ed candidate therapeutics that at low concentrations inhibit growth of cancer cells expressing high ZNF217. We show that the nucleoside analogue triciribine inhibits ZNF217-induced tumor growth and chemotherapy resistance and inhibits signaling events [e.g., phospho-AKT, phospho-mitogen-activated protein kinase (MAPK)] in vivo. Our data suggest that ZNF217 is a biomarker of poor prognosis and a therapeutic target in patients with breast cancer and that triciribine may be part of a personalized treatment strategy in patients overexpressing ZNF217. Because ZNF217 is amplifi ed in numerous cancers, these results have implications for other cancers. SIGNIFICANCE: This study finds that ZNF217 is a poor prognostic indicator and therapeutic target in patients with breast cancer and may be a strong biomarker of triciribine treatment efficacy in patients. Because previous clinical trials for triciribine did not include biomarkers of treatment efficacy, this study provides a rationale for revisiting triciribine in the clinical setting as a therapy for patients with breast cancer who overexpress ZNF217.

Original languageEnglish (US)
Pages (from-to)638-651
Number of pages14
JournalCancer Discovery
Volume2
Issue number7
DOIs
StatePublished - Jul 2012

ASJC Scopus subject areas

  • Oncology

Fingerprint Dive into the research topics of 'The transcription factor ZNF217 Is a prognostic biomarker and therapeutic target during breast cancer progression'. Together they form a unique fingerprint.

  • Cite this

    Littlepage, L. E., Adler, A. S., Kouros-Mehr, H., Huang, G., Chou, J., Krig, S. R., Griffi th, O. L., Korkola, J. E., Qu, K., Lawson, D. A., Xue, Q., Sternlicht, M. D., Dijkgraaf, G. J. P., Yaswen, P., Rugo, H. S., Sweeney, C. A., Collins, C. C., Gray, J. W., Chang, H. Y., & Werb, Z. (2012). The transcription factor ZNF217 Is a prognostic biomarker and therapeutic target during breast cancer progression. Cancer Discovery, 2(7), 638-651. https://doi.org/10.1158/2159-8290.CD-12-0093