Background: ZNF217 is found amplified at the 20q13.2 locus in 20% of breast tumors. Recent work suggests that ZNF217 may encourage neoplastic transformation by promoting cell survival through aberrant transcriptional regulation of genes upstream of the PI3K pathway. An unbiased, functional genomics approach was used to identify potential ZNF217 gene targets, among them the ErbB3 receptor tyrosine kinase.) Our work demonstrates a strong positive correlation between ZNF217 and ErbB3 expression in breast tumors supported by gain and loss of function cell culture studies (manuscript in press). This suggests a novel mechanism for ErbB3 overexpression. Importantly, ErbB3 potently activates the PI3K pathway, driving tumor cell survival and invasion. Preliminary results, modeling ZNF217 amplification in MCF10A 3D matrigel culture suggest an aggressive phenotype. The concept that ZNF217 positively regulates ErbB3 expression, contributing to survival and invasiveness of tumors with 20q13 amplification, is innovative. Knowledge that a significant number of breast tumors are amplified at the 20q13 locus containing ZNF217, suggests utility as an early biomarker for invasive disease.
Hypothesis: The 20q13.2 locus is associated with aggressive features (high histological grade, DNA aneuploidy, high S-phase fraction, axillary nodal involvement). We will explore ZNF217 overexpression as a surrogate marker for 20q13 amplification and a potential biomarker for prediction of invasive potential and metastatic disease. Preliminary array Comparative Genomic Hybridization (aCGH) identified a significant number of 20q13-amplified breast tissue samples with increased ZNF217 copy numbers. We hypothesize that breast tissue samples taken at the time of biopsy could be assayed for amplified ZNF217 and will predict cancers with trajectory towards aggressive disease. This comprehensive study will report the association between 20q13 amplification, ZNF217 copy number, and ZNF217 nuclear expression. Employing ZNF217 immunohistochemistry (IHC), as a clinical test similar to the HercepTest, could simultaneously screen for 20q13-positive and ZNF217-positve breast tumors providing valuable prognostic information.
Study: To examine overlap for ZNF217 amplification at 20q13 and ZNF217 overexpression, paraffin-embedded breast tissue samples (with 10 years follow-up data) will be screened using aCGH to identify 100 samples that are 20q13-amplified and 50 specimens with no extra copies. The ZNF217 copy number will be determined using aCGH analysis software. To determine ZNF217 protein levels in the 20q13-amplified or nonamplified samples, IHC will be performed and nuclei scored for positivity by blinded pathologists. Statistical analysis will determine the significant correlation and potential for ZNF217 as a surrogate marker for amplified 20q13. ZNF217 positivity will be correlated with poor patient prognosis including progression to IDC or development of distant metastases as well as disease-free and overall survival. In addition, we will correlate ZNF217 levels with other prognostic factors; PR, ER, HER2, and lymph node status. Impact on breast cancer: We propose that ZNF217, amplified at 20q13, may provide prognostic value and stratification of tumors, predicting aggressive lesions at early stages of breast tumor development. Widespread use of mammography in breast cancer screening has led to earlier detection, identifying patients with preinvasive disease. Biomarkers that will accurately predict the propensity of a tumor to progress to invasive disease are needed to provide opportunities for early and aggressive therapy when warranted; avoiding drastic measures when unnecessary. Our study will determine if ZNF217 will be a useful biomarker that can be immediately introduced into the clinic with routine, inexpensive IHC assay at the time of biopsy.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A30.