Zinc Finger Transcription Factors as Novel Genetic Switches to Modulate Metastatic Progression of Breast Tumors

摘要

The transcriptional programs cooperatively required for the malignant progression of breast tumors are largely unknown. In this project we propose the isolation of Artificial Transcription Factors (TFs) for the discovery of gene panels, which cooperate during the generation of metastatic behavior. An ATF is made by linkage of a DNA-binding domain (DBD) with a transcriptional effector domain, which mediates activation or repression of endogenous genes. ATFs are typically made of arrays of Cys2-His2 zinc finger (ZF) domains. The objective of this proposal is to apply large ATF libraries to identify and regulate genes that cooperate during the process induction of breast cancer cell invasion and progression. We have delivered ATF libraries into non-invasive breast cancer cell lines. We have selected ATFs able to induce or enhance breast cell invasion. The ATF-selections were performed in vitro using matrigel invasion assays (Boyden chambers). ATFs modulating cell invasion were profiled using DNA microarrays to determine genes differentially regulated by the ATF that are responsible for the phenotype change.