College of Osteopathic Medicine Faculty Articles


Nucleotide Excision Repair Deficiency is Intrinsic in Sporadic Stage I Breast Cancer



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Proceedings of the National Academy of Sciences USA





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The molecular etiology of breast cancer has proven to be re- markably 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 instabil- ity, a hallmark of carcinogenesis. By microarray analysis, mRNA ex- pression levels for 20 canonical NER genes were reduced in repre- sentative 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 eti- ology of sporadic breast cancer, and that early-stage breast can- cer 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 iden- tification of tumorigenic breast epithelium.


Medical Specialties | Medicine and Health Sciences | Osteopathic Medicine and Osteopathy

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