Nucleotide Excision Repair Identifies Two Distinct Types of Non-Tumor Adjacent Breast in Sporadic, Non-Germline Breast Cancer

Nova Southeastern University, Davie, Florida, USA

Objective: Establish molecular temporal scheme for changes leading to breast cancer using Nucleotide Excision Repair (NER) capacity of early stage tumors and their isogenically matched non-tumor adjacent (NTA) samples. Background: Loss of DNA repair capacity leads to genomic instability, a hallmark of carcinogenesis. Sporadic stage I breast tumors are intrinsically deficient in their NER capacity relative to non-diseased breast, the regulation of which is thought to be primarily epigenetic. We previously identified two groups of NTA tissue explants based on their NER capacities as measured by the functional Unscheduled DNA Synthesis (UDS) assay. 25% of NTA had normal NER capacity, similar to that of BRE, but higher than their matched stage I tumors (High-Low pair), whereas 75% exhibited lower NER capacity relative to BRE and similar to the matched tumor (Low-Low pair). We hypothesized that epigenetic regulation of NER genes would explain these different types of NTA. Methods: The functional UDS assay was used to select cell line pairs established by the Latimer Lab’s tissue engineering system, representing the two groups. Expression of 20 canonical NER genes was measured by microarray analyses and confirmed with RNA sequencing. Results: The expression pattern of NER genes was concordant with their NER capacity in both types NTA and tumors. RNA sequencing confirmed these findings. Conclusion: The NTA breast represents a preneoplastic stage in breast carcinogenesis. Two different types of NTA have been identified with regard to DNA repair. Grants: NSU’s PFRDG (6/1/12–5/31/14), NIH R29 (PI: Jean Latimer), NSU’s PFRDG (6/1/13-5/31/15)