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

• Published in: Oncogene Vol. 29; no. 40; pp. 5500 - 5510
• Main Authors: Krig, S R, Miller, J K, Frietze, S, Beckett, L A, Neve, R M, Farnham, P J, Yaswen, P I, Sweeney, C A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07-10-2010; Nature Publishing Group
• Subjects: 631/208/200; 631/67/395; 631/80/86; 692/699/67/1347; AKT protein; Animals; Apoptosis; Biological and medical sciences; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cancer cells; Cell Biology; Cell Line, Tumor; Cell physiology; Cell receptors; Cell structures and functions; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular biology; Chromatin Immunoprecipitation; Chromosomes, Human, Pair 20 - genetics; Development and progression; Ectopic expression; Epithelial cells; ErbB-2 protein; ErbB-3 protein; Female; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene Expression Regulation, Neoplastic - genetics; Gene silencing; Genes, erbB - genetics; Genetic aspects; Gynecology. Andrology. Obstetrics; Human Genetics; Humans; Internal Medicine; Kinases; Mammary gland; Mammary gland diseases; Medical sciences; Medicine; Medicine & Public Health; Mice; Mice, Transgenic; Miscellaneous; Molecular and cellular biology; Oligonucleotide Array Sequence Analysis; Oncogenes; Oncology; original-article; Physiological aspects; Promoter Regions, Genetic; Properties; Protein-tyrosine kinase receptors; Receptor, ErbB-3 - biosynthesis; Receptor, ErbB-3 - genetics; Reverse Transcriptase Polymerase Chain Reaction; Signal transduction; Signal Transduction - genetics; Trans-Activators - genetics; Trans-Activators - metabolism; Tumor cell lines; Tumors; United States; ZNF217; breast cancer; 20q13; CtBP2; ErbB3; Breast disease; Enzyme; Transferases; Breast cancer; Malignant tumor; Carcinogenesis; Mammary gland diseases; Regulation(control); C-Onc gene; Onc gene; Protein-tyrosine kinase; Cancer; Biological receptor
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2010.289

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.