Nucleotide excision repair deficiency is intrinsic in sporadic stage I breast cancer

Abstract

The molecular etiology of breast cancer has proven to be remarkably complex. Most individual oncogenes are disregulated in only approximately 30% of breast tumors, indicating that either very few molecular alterations are common to the majority of breast cancers, or that they have not yet been identified. In striking contrast, we now show that 19 of 19 stage I breast tumors tested with the functional unscheduled DNA synthesis assay exhibited a significant deficiency of DNA nucleotide excision repair (NER) capacity relative to normal epithelial tissue from disease-free controls (n = 23). Loss of DNA repair capacity, including the complex, damage-comprehensive NER pathway, results in genomic instability, a hallmark of carcinogenesis. By microarray analysis, mRNA expression levels for 20 canonical NER genes were reduced in representative tumor samples versus normal. Significant reductions were observed in 19 of these genes analyzed by the more sensitive method of RNase protection. These results were confirmed at the protein level for five NER gene products. Taken together, these data suggest that NER deficiency may play an important role in the etiology of sporadic breast cancer, and that early-stage breast cancer may be intrinsically susceptible to genotoxic chemotherapeutic agents, such as cis-platinum, whose damage is remediated by NER. In addition, reduced NER capacity, or reduced expression of NER genes, could provide a basis for the development of biomarkers for the identification of tumorigenic breast epithelium.human primary breast cell explant culture | human breast tumor explant culture | breast epithelial attached epispher | hypermutability

Formaldehyde induces toxic effects and regulates the expression of damage response genes in BM-MSCs

“…The NER pathway is an important pathway for DNA damage repair, which mainly repairs the cyclobutane pyrimidine dimer, DNA adducts, and cross-linking between chains [33,34]. HR refers to the recombination of homologous DNA sequences, which mainly uses the homology of DNA sequences for recognition.…”

DNA repair and damage pathways in breast cancer development and therapy

“…Finally, the damaged site is restored by complexes consisting of DNA-Polδ/ε, RFC, and PCNA or, DNA-Polδ/ε and XRCC1 [70]. NER deficiency and its potential in the etiology of breast cancer was investigated in a study by Latimer et al [71], who showed a significant deficiency of NER capacity in stage I breast tumors relative to normal disease-free epithelial tissue, as tested by the functional unscheduled DNA synthesis assay. In tumor samples, the expression of 20 genes in NER pathway was decreased compared to normal tissue.…”

Unscheduled DNA Synthesis: The Clinical and Functional Assay for Global Genomic DNA Nucleotide Excision Repair

“…More recently, there are also PCR-based assays ( see Chapter 31), and flow cytometry-based assays [21, 22]. Recent studies using the UDS protocol in this chapter include functional analyses of primary cultures of human lymphocytes, breast and ovarian tissue, and early-stage breast tumors [23–26]. …”