Regulation of Metastasis and DNA Damage Resistance Pathways by Transposable Elements.

摘要

Understanding molecular pathways that control resistance to chemotherapy/radiation and regulate metastasis are critical to improving breast cancer survival. We have been characterizing the biology behind gene signatures that either promotes DNA damage resistance or metastasis. Interestingly, these gene signatures are often populated with interferon-stimulated genes or pro-inflammatory mediators that respond to viral infection. This raises the question of what is behind the perplexing relationship between anti-viral responses and breast cancer progression. For this, we are focusing on the potential role of transposable elements (TEs), which are small pieces of DNA that have the ability to move within the genome and are often referred to as "jumping genes". Interestingly, expression of genes belonging to DNA damage resistance gene signatures are also induced after DNA damage and expression often associates with aberrant TE expression. These data raise the intriguing possibility that various pattern-recognition receptors (PRRs) that normally sense viral and bacteria nucleic acids and signal to interferon and pro-inflammatory pathways may provide a link between TE de-repression and expression of resistance and metastasis genes. Thus, the purpose of our Collaborative Idea Award proposal is to begin to explore the mechanisms of TE de-repression by DNA damage responses, how aberrant TEs are sensed, and the consequences of this on resistance.