Title

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

ISBN or ISSN

1091-6490

Publication Title

Proceedings of the National Academy of Sciences of the United States of America

Volume

107

Issue

50

Publication Date / Copyright Date

12-14-2010

First Page

21725

Last Page

21730

Publisher

National Academy of Sciences

DOI Number

10.1073%2Fpnas.0914772107

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.

Disciplines

Medicine and Health Sciences | Pharmacy and Pharmaceutical Sciences

Keywords

Adult, Aged, Aged, 80 and over, Breast Neoplasms, DNA Damage, DNA Repair, Female, Humans, Microarray Analysis, Middle Aged, RNA, Messenger