I have applied our high-throughput genomic/epigenomic technologies, such as high-density SNP arrays and next-generation sequencing (NGS) technology, to identifying genes that present as plausible candidates for contributing to breast cancer development. The genomic investigation has led to the identification of two putative oncogenes, IRX2 and TBL1XR1. These two genes initially attracted my attention because they function in transcriptional regulation and chromatin dynamics, which is a major theme of my research program. Our immunohistochemistry (IHC) studies showed that IRX2 and TBL1XR1 were frequently over-expressed in breast tumors (versus no expression in normal cells). To date, our research has provided direct experimental evidence supporting an oncogenic effect for TBL1XR1. We used the shRNA approach to knock down the expression of TBL1XR1 in breast cancer cells and found that depletion of the TBL1XR1 protein in the cells reduced cell migration/invasion and suppressed tumor growth in mouse xenografts. Our epigenomic investigation has led to the identification of DNA methylation signatures that are selectively associated with clinical phenotypes such as lymph node involvement, histological grade, tumor size, and ER/PR/HER2 status. As an example, we observed specific DNA methylation signature that distinguishes primary breast cancer samples diagnosed as high-grade from those diagnosed as low-mid-grade tumors. Our recent studies with NGS have identified hundreds of point mutations, chromosome rearrangements, and novel splicing isoforms that are associated with tumors and/or specific tumor subtypes, such as triple negative tumors.
