Molecular Mechanism of DNA Repair Deficiency in Breast Cancer

Grant Winners

Dean

Abstract

Breast cancer is a common disease, with nearly 200,000 newly diagnosed cases annually in the U.S., with a similar frequency in Europe. Because breast cancer can affect younger women, and these women are frequently the core caregivers of their families, its impact is powerful on a societal as well as a medical level. While the molecular mechanism of breast cancer has been studied extensively, no universal set of genes have been identified in non-hereditary, sporadic cancer, which represents 90% of all cases. Instead, many genes have been identified as being altered in expression or integrity in breast cancer. We have taken a fundamentally different approach to investigate the basis of breast cancer, by analyzing what is functionally wrong with the cells that we directly culture from breast tumors when compared with cultures of normal, non-diseased control breast tissue from the same women. We recently published a PNAS paper showing that DNA repair is significantly reduced in stage I (early) breast tumors compared with non-diseased breast tissue. We further showed that the RNA and protein expression of 19 out of 20 of the canonical genes in the Nucleotide Excision DNA Repair pathway are reduced in tumors relative to normal breast tissue. We would now like to understand how these genes are all being down-regulated. Our primary hypothesis is that these genes are downregulated because of the presence of specific non-coding regulatory microRNAs (miRNAs) that can bind the genes in the 3í untranslated regions or in other areas of the gene. If so, these microRNAs may represent a druggable method of treatment for certain forms of breast cancer. If miRNAs are not found to be the cause, we will explore whether methylation of the regulatory regions of these genes is responsible for this concerted down-regulation of DNA repair genes.