Amplification at 20q13.2 is frequently observed in breast cancer and is associated with aggressive tumor behavior and poor prognosis. A positional cloning strategy was employed to identify the hypothesized oncogene that culminated in the molecular cloning of ZNF217. ZNF217 is over expressed in all tumors and cell lines in which it is amplified and some in which it is not. Sequence analysis revealed ZNF217 to be a member of the Kruppel gene family indicating that it may function, in part, as a transcription factor. Intensive efforts have been made to understand the role of ZNF217 in breast cancer by determining the effect of its' overexpression in human mammary epithelial cells (HMECs) and identification of ZNF217 protein binding partners. Ectopic expression of ZNF217 immortalizes HMECs and is accompanied by induction of telomerase activity. A yeast two-hybrid screen identified hnRNPK and M2PK as ZNF217 protein binding partners suggesting that ZNF217 may play an important role in breast carcinogenesis by subverting both metabolic and transcriptional pathways. In particular ZNF217 may cooperate with hnRNPK to transactivate CMYC and turn on telomerase activity while its interaction with M2PK expands metabolite pools and lowers tumor oxygen requirements. To fully understand ZNF217's role in breast carcinogenesis the protein domains responsible for ZNF217-hnRNPK and ZN217-M2PK interaction will be determined and binding mutants engineered. As part of this study it will be established whether the wild- type and mutant proteins co-localize in immortalized HMECs and other breast cancer cell lines. The effect of ZNF217 binding M2PK in HMECs will be assessed by measuring M2PK isoform ratios and cellular metabolism. Finally, it will be determined if ZNF217 mediated HMEC immortalization occurs through the CMYC pathway or an independent mechanism. Knowledge of the specific pathways ZNF217 functions in and its protein binding partners will have a profound impact on our understanding of tumor biology and will provide critical insights regarding diagnostic and therapeutic approaches to breast cancer. Indeed, these studies have already led to a collaboration investigating the utility of M2PK as a diagnostic marker for breast and ovarian cancer and the NCI-Bay Area SPORE is committed to exploring the therapeutic potential of the proposed model.
| Huang, Guiqing; Krig, Sheryl; Kowbel, David et al. (2005) ZNF217 suppresses cell death associated with chemotherapy and telomere dysfunction. Hum Mol Genet 14:3219-25 |
