Epigenomics of Transcriptional Regulation in Breast Cancer
Research in the Lupien Laboratory focuses on understanding how transcriptional programs are established in breast cancers by studying cistromes, epigenomes and genetic variations. This is achieved through the use of next generation sequencing technologies coupled to chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP) and ncRNA/miRNA/mRNA profiling.
Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related deaths in North American women. The estrogen receptor alpha (ER) is a transcription factor central in the development of more than two-thirds of breast cancers. It directly contributes to altered gene expression profiles typical of luminal breast cancer subtypes. Accordingly, therapeutic intervention involves agents that block the receptor's actions. Unfortunately, ~40% of breast cancers are tolerant or acquire resistance to these endocrine therapies.
One of our research interests is to determine how epigenetic events that affect chromatin accessibility contribute to ER-mediated transcriptional reprogramming in breast cancers. We have previously demonstrated that chromatin needs to be marked in a lineage-specific manner by histone H3 lysine 4 methylation (H3K4me). This is required to restrict transcription factor recruitment and activity in different cell types. Part of our current research focuses on the mechanisms associated with the lineage-specific deposition of this epigenetic event.
A second research interest deals with aims to define the function of an emerging class of DNA binding proteins known as pioneer factors. We previously demonstrated the central role for the pioneer factor FoxA1 in remodeling the chromatin and guiding transcription factor activity. Our current research is identifying novel pioneer factors and characterizing their role in breast cancer.
A third research interest focuses on defining how genetic variations affect transcription in breast cancer. Sequencing efforts have identified close to 20 millions genetic variations across the human genome. Some increase the risk of developing breast cancer. We are currently combining different "omics" datasets to determine their role in promoting breast cancer development and progression.