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

Understanding the mechanisms underlying ErbB3 over-expression in breast cancer will facilitate the rational design of therapies to disrupt ErbB2-ErbB3 oncogenic function. While ErbB3 over-expression 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 over-expression is achieved. In this study we demonstrate 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) demonstrated a strong positive correlation between ZNF217 and ErbB3 expression. Ectopic expression of ZNF217 in human mammary epithelial cells induced ErbB3 expression while ZNF217 silencing in breast cancer cells resulted in decreased ErbB3 expression. While ZNF217 has previously been linked with transcriptional repression due to its close association with CtBP1/2 repressor complexes, our results demonstrate that ZNF217 also activates gene expression. We demonstrate that ZNF217 recruitment to the ErbB3 promoter is CtBP1/2-independent and that ZNF217 and CtBP1/2 play opposite roles in regulating ErbB3 expression. In addition, we identify ErbB3 as one of the mechanisms by which ZNF217 augments PI-3K/Akt signaling.