Research in this laboratory is focused on cancer gene discovery using pathway-based candidacy techniques and characterization of the biological roles of such genes in cacinogenesis. Our primary focus has been on the AXIN2 gene. We previously isolated this gene, identified truncating mutations of this gene in ~25% of colorectal cancer (CRC) with defective MSI, and demonstrated that mutant AXIN2 activates TCF signaling. Recently, germline AXIN2 mutations were also reported in familial CRC families. However, the cellular function of AXIN2 and how its inactivation contributes to cancer remains unknown. We are currently using several approaches to study AXIN2 function, including 1) studies of the regulation of AXIN2 in normal and tumor tissues; 2) identification and characterization of proteins specifically bind to the C-terminus of AXIN2; 3) isolation and characterization of AXIN2 regulated genes; and 4) generation of AXIN2 "knockout" mouse to elucidate the role of this protein in vivo.

My laboratory is also engaged in the identification and characterization of prostate cancer susceptibility genes. We have identified germline mutations in several DNA damage-signaling pathway genes, such as CHK2 in prostate cancer patients, and shown that the individuals carrying the mutant alleles of these genes have increased risk to develop prostate cancer. We also demonstrated that cells carrying such mutant alleles either lose their abilities to respond to DNA damage or to induce apoptosis. Our current efforts are aimed at identifying additional prostate cancer susceptibility genes in the same pathway and characterizing the roles of such genes in prostate cancer carcinogenesis. It is anticipated that this work will provide more information in identifying men at increased risk of prostate cancer development in whom prevention strategies might be targeted.