Gene regulatory elements as breast cancer susceptibility loci and biomarkers (#3)
Aberrant expression of cancer-associated genes contributes to initiation and progression of the tumourigenic process. Such changes in gene expression result from defects in transcriptional control elements, including promoters and enhancers, and in post-transcriptional control elements, including those found in the 3’UTR. Epigenetic defects include methylation of transcriptional regulatory elements and altered targeting of post-transcriptional regulatory elements by trans-acting factors including microRNAs. Our group has a long-standing interest in elucidating the genetic and epigenetic regulation of breast cancer associated genes, including BRCA1. Our studies have led to the identification of regulatory sequences mapping to promoter, intronic, 3’UTR and extragenic sequences of BRCA1, and the promoter of AR and a number of miRNAs, including miR-200b. We have also identified proteins and miRNAs that target these sequences, including the RNA binding protein HuR, which targets the BRCA1 3’UTR. We have shown that genetic and epigenetic changes in these sequences, some of which are associated with breast cancer susceptibility and progression, affect gene expression and are sometimes associated with altered targeting by proteins or miRNAs. We have also identified a number of miRNAs that are differentially expressed in the pre-malignant mammary glands of a BRCA1-associated breast cancer mouse model. Current studies involve elucidating the mechanism of this regulation and the role of these events in mammary tumourigenesis and the clinical utility of these regulatory elements and events as biomarkers of cancer susceptibility and progression.