My laboratory investigates the transcriptional control of the urokinase receptor (u-PAR) gene the product of which contributes to the spread of cancer. We are using transgenic mice and DNaseI hypersensitivity assays to identify novel regions driving tissue-specific u-PAR expression in animals genetically induced for colon cancer. We are also determining which chromatin modifications (focusing on histone phosphorylation) lead to elevated u-PAR expression in invasive cancers.

It is now evident that tumor development/progression reflects the combinatorial action of multiple gene products, each providing some “fitness advantage.” In data-mining for transcripts over expressed in colon cancer, we identified ESTs corresponding to a novel zinc finger protein (ZKSCAN3) as over-represented in this malignancy. 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 bladder cancer progression. The predicted ZKSCAN3 protein sequences includes domains (tandem zinc fingers, KRAB domain) typically present in proteins regulatory for gene expression. Using unbiased methods (CAST-ing and expression profiling) we identified putative downstream effectors.

 

In addition to the abovementioned basice science projects, we are also pursuing a joint epidemiology/clinical project with investigators at the USAF School of Aerospace Medicine and the University of Texas Health Science Center in Houston/San Antonio. We have determined that the majority of prostate cancers diagnosed in active duty USAF servicemen are categorized as low-risk. Our project seeks to determine (a) what is the natural history of low-risk disease in servicemen who opt for active surveillance (b) for those who elect for intervention, what type of treatment is selected and the reason(s) for the choice.