TF Isoforms
One of the ultimate goals of cancer systems biology is to generate predictive and dynamic models of tumorigenesis by identifying and quantifying all perturbed functional interactions in a cancerous cellular system. Genome alterations such as amplification, deletion, translocations and mutations, are often considered primary events of cancer progression. However, cancer-specific isoforms resulting from alternative splicing, alternative sites of transcriptional initiation, and/or alternative transcriptional termination sites, have also been shown to have functional impact on tumorigenesis. In particular, changes in gene regulatory networks (GRNs) by TF isoforms have been shown to play a major role in tumorigenesis and metastasis in multiple types of cancer. Hundreds of differential TF isoforms have been identified between normal and cancer samples, but the vast majority remain uncharacterized at the functional level. While a few examples of functional characterization of driver cancer-specific TF isoforms have been reported, the extent to which the expression of TF isoforms differs between normal and cancer tissues and how such differences may lead to altered gene expression programs in cancer, remains unclear.
Together with collaborators, we are investigating the regulatory consequences of TF isoforms in human breast cancer. In the Bulyk lab, we are characterizing the DNA binding activities of TF isoforms for differences in their recognition of DNA targets. We are also developing high-throughput functional assays of the impact of TF isoforms on phenotypes in breast cancer cell lines. The results from these studies and their integration with the impact of TF isoforms on protein-protein interactions and transcriptional activation or repression activity, will lead to the identification of novel cancer drivers and suppressors and the generation of mechanistic models of GRN rewiring in breast cancer.