Loss of Nucleotide Excision Repair as a Source of Genomic Instability in Breast Cancer
Abstract
Genomic instability is a hallmark of carcinogenesis in human tumors, including sporadic and familial breast cancer. A major source for genomic instability are defects in mechanisms for the repair of DNA damage or errors in replication. We recently reported that the breast cancer susceptibility gene BRCA1 is directly involved in the regulation of global genomic nucleotide excision repair (NER) through its ability to transcriptionally regulate DNA damage recognition genes. Several lines of evidence suggest that an altered ability to repair DNA adducts due to cellular defects in NER may be a common source for genomic instability in preneoplastic breast tissue, resulting in enhanced mutagenesis of other cancer genes and breast cancer progression. Therefore, we are studying NER activity in primary breast epithelial cells and breast cancer tissues from women at risk for or diagnosed with breast cancer, as well as in mammary epithelial cells from mice as model system. We will take advantage of our high-risk breast cancer clinic, where we currently have ongoing clinical protocols using ductal lavage, random periareolar fine needle aspiration (rpFNA) and MRI directed biopsies to screen women for early breast cancer and to study the genetics of breast epithelial cells. We hypothesize that altered NER activity may be a common, initial and detectable event leading to genomic instability in human breast epithelial cells, ductal carcinoma in situ, or early invasive breast cancers. We will study NER in preneoplastic breast tissue from high and low risk individuals, BRCAl mutation carriers and others, and invasive breast cancer tissue, using novel cell based functional assays of DNA repair. Our studies may allow, for the first time, a direct assessment of NER activity in primary breast tissue.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2005
- Accession Number
- ADA437914
Entities
People
- James M. Ford
Organizations
- Stanford University