The Transcription Factor ZNF217 Is a Prognostic Biomarker and Therapeutic Target during Breast Cancer Progression

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 identified 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 amplified 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.

Genetic and molecular alterations in olfactory neuroblastoma: implications for pathogenesis, prognosis and treatment

“…In clear cell ovarian carcinoma ZNF217 overexpression was strongly related to poor prognosis upon platinum agent-based chemotherapy [61]. ZNF217 suppresses chemotherapy-induced cell death, promoting doxorubicin and paclitaxel resistance in breast cancer [87, 88]. Triciribine, a nucleoside analog and AKT inhibitor effectively kills chemoresistant cancer cells overexpressing ZNF217 [87].…”

“…ZNF217 suppresses chemotherapy-induced cell death, promoting doxorubicin and paclitaxel resistance in breast cancer [87, 88]. Triciribine, a nucleoside analog and AKT inhibitor effectively kills chemoresistant cancer cells overexpressing ZNF217 [87]. As chemotherapy in ONB is often based on cisplatin, antracyclines and taxanes, triciribine may be potentially useful in overcoming resistance to these agents.…”

Presence of Insulin-Like Growth Factor Binding Proteins Correlates With Tumor-Promoting Effects of Matrix Metalloproteinase 9 in Breast Cancer

“…Survival analysis based on expression levels of MMP9 and IGFBP s was conducted as previously described [33]. Briefly, signal intensities of each probe were acquired from the Gene Expression Omnibus database and analyzed by Expression Console software (Affymetrix, Santa Clara, CA).…”

ZNF217/ZFP217 Meets Chromatin and RNA

“…The ZNF217 gene is located at the 20q13 chromosomal region that is commonly amplified in various human cancers, and the expression of ZNF217 is strongly associated with poor clinical prognosis [1, 2]. Mammary epithelial tumor cells ectopically expressing ZFP217 and transplanted into mammary fad pads of immune compromised mice resulted in increased tumor burden [3]. These observations suggested ZNF217/ZFP217 to be pro-oncogenic.…”

“…First, ZNF217/ZFP217 has been suggested to regulate oncogenic gene expression by acting as a transcriptional repressor of tumor suppressor genes [2]. Second, ZNF217/ZFP217 may also promote cancer progression and pluripotency by activating the expression of pro-oncogenic genes and core stem cell transcripts, respectively [3, 4]. Third, ZFP217 was found to restrict m 6 A deposition at pluripotency RNAs, protecting such transcripts from rapid degradation [5].…”