Genetic Analysis of DNA Repair Deficiency in Novel Non-Tumor Adjacent and Tumor Cell Cultures Suggests a New Paradigm of Breast Cancer Etiology
Abstract
Objective. This study was conducted to determine the basis for the deficiency in DNA nucleotide excision repair (NER) that we have documented in stage I breast tumors. Background. One of the hallmarks of cancer is genetic instability, which can arise through loss of DNA repair. Using the functional assay for “unscheduled DNA synthesis” (UDS), we determined that stage I breast tumors had significantly less NER capacity (47%) than normal breast epithelium. Methods. Our laboratory has developed a novel tissue engineering system for human breast tissue, both normal and malignant. In order to study the loss of DNA repair as an etiological factor in breast cancer etiology, we generated over 20 matched pairs of cell lines from human breast tumors and isogenic non-tumor adjacent (NTA) tissue, without the use of immortalizing agents. Results. UDS analysis revealed that 75% of our NTA primary cultures (N = 42) manifest the same NER deficiency as the matching tumor culture. Conclusion. In the majority of breast tumors loss of NER preceded the final mutation(s) that led to full blown transformation. An area of predisposed tissue remains around the tumor itself that can contribute to tumor “recurrence.” We believe that NTA cultures with aberrations, such as deficient DNA repair, in common with the tumor represent 29 opportunities to investigate early changes during carcinogenesis, and can act as experimental models for later steps through promotion or genetic transformation. Grants. This study was partially supported by grants from the DOD CDBCRP and Susan G. Komen for the Cure.
Genetic Analysis of DNA Repair Deficiency in Novel Non-Tumor Adjacent and Tumor Cell Cultures Suggests a New Paradigm of Breast Cancer Etiology
Objective. This study was conducted to determine the basis for the deficiency in DNA nucleotide excision repair (NER) that we have documented in stage I breast tumors. Background. One of the hallmarks of cancer is genetic instability, which can arise through loss of DNA repair. Using the functional assay for “unscheduled DNA synthesis” (UDS), we determined that stage I breast tumors had significantly less NER capacity (47%) than normal breast epithelium. Methods. Our laboratory has developed a novel tissue engineering system for human breast tissue, both normal and malignant. In order to study the loss of DNA repair as an etiological factor in breast cancer etiology, we generated over 20 matched pairs of cell lines from human breast tumors and isogenic non-tumor adjacent (NTA) tissue, without the use of immortalizing agents. Results. UDS analysis revealed that 75% of our NTA primary cultures (N = 42) manifest the same NER deficiency as the matching tumor culture. Conclusion. In the majority of breast tumors loss of NER preceded the final mutation(s) that led to full blown transformation. An area of predisposed tissue remains around the tumor itself that can contribute to tumor “recurrence.” We believe that NTA cultures with aberrations, such as deficient DNA repair, in common with the tumor represent 29 opportunities to investigate early changes during carcinogenesis, and can act as experimental models for later steps through promotion or genetic transformation. Grants. This study was partially supported by grants from the DOD CDBCRP and Susan G. Komen for the Cure.