My laboratory investigates the transcriptional control of genes that contribute to the spread of cancer. One of these genes, the urokinase receptor (u-PAR), is overexpressed in colon cancer. We are using transgenic mice and DNaseI hypersensitivity assays to identify novel regions driving tissue-specific u-PAR expression both in healthy mice and animals genetically induced for colon cancer, the latter allowing an analysis of transcriptional requirements in colon cancer in vivo. Also, we are employing expression cloning and siRNA library strategies to identify novel regulators of u-PAR expression, and, to date, we have identified two hitherto unknown regulators of their expression, i.e., KLF4 and SM22, respectively.

In this post-genomic era, it is now evident that tumor development/progression reflects the combinatorial action of multiple gene products, each providing some “fitness advantage.” In an agnostic approach, data-mining ( UniGene Cluster Expression) for transcripts over expressed in colon cancer, revealed over-representation of ESTs corresponding to a novel zinc finger protein (ZKSCAN3). We pursued ZKSCAN3 as a candidate transcript contributing to tumor development/progression as the gene resides in a chromosomal region (6p22.1) that shows gain/amplification in colon, bladder and prostate cancers. Using genetic models (ZKSCAN3 transgenic and null mice) we will determine if expression of the zinc finger protein alone, or with a mutated APC, contributes to intestinal tumor development/progression. Conversely, do mice null for ZKSCAN3 show low colon tumor development in response to azoxymethane or the new Western diet? We will also determine the role of ZKSCAN3 in prostate/bladder cancer progression. The predicted ZKSCAN3 protein sequences includes domains (tandem zinc fingers, KRAB domain) typically present in proteins regulatory for gene expression. Towards determining a mechanism, using unbiased methods (CAST-ing and expression profiling) we have identified putative downstream effects which we are presently validating.