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

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 ident...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 107; no. 50; pp. 21725 - 21730
Main Authors Latimer, Jean J., Johnson, Jennifer M., Kelly, Crystal M., Miles, Tiffany D., Beaudry-Rodgers, Kelly A., Lalanne, Nancy A., Vogel, Victor G., Kanbour-Shakir, Amal, Kelley, Joseph L., Johnson, Ronald R., Grant, Stephen G., Cleaver, James E.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 14.12.2010
National Acad Sciences
Subjects
Adult
Aged
Aged, 80 and over
Biological Sciences
Biomarkers
Breast cancer
Breast neoplasms
Breast Neoplasms - etiology
Breast Neoplasms - genetics
Breast Neoplasms - pathology
Cancer
Carcinogenesis
Cell lines
Deoxyribonucleic acid
DNA
DNA Damage
DNA Repair
Epithelial cells
Female
Gene expression
Genes
Genomics
Humans
Microarray Analysis
Middle Aged
Pathology
RNA, Messenger - genetics
RNA, Messenger - metabolism
Tumors
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Summary: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.
Bibliography:Edited* by James E. Cleaver, University of California, San Francisco, CA, and approved November 1, 2010 (received for review December 23, 2009)
Author contributions: J.J.L., J.M.J., and S.G.G. designed research; J.M.J., C.M.K., T.D.M., K.A.B.-R., N.A.L., and A.K.-S. performed research; J.J.L., V.G.V., J.L.K., and R.R.J. contributed new reagents/analytic tools; J.J.L., J.M.J., C.M.K., N.A.L., and S.G.G. analyzed data; and J.J.L., J.M.J., and S.G.G. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0914772107