Regulation and disregulation of mammalian nucleotide excision repair: a pathway to nongermline breast carcinogenesis.
Nucleotide excision repair (NER) is an important modulator of disease, especially in constitutive deficiencies such as the cancer predisposition syndrome Xeroderma pigmentosum. We have found profound variation in NER capacity among normal individuals, between cell-types and during carcinogenesis. NER is a repair system for many types of DNA damage, and therefore many types of genotoxic carcinogenic exposures, including ultraviolet light, products of organic combustion, metals and oxidative stress. Because NER is intimately related to cellular metabolism, requiring components of both the DNA replicative and transcription machinery, it has a narrow range of functional viability. Thus, genes in the NER pathway are expressed at the low levels manifested by, for example, nuclear transcription factors. As NER activity and gene expression vary by cell-type, it is inherently epigenetically regulated. Furthermore, this epigenetic modulation is disregulated during sporadic breast carcinogenesis. Loss of NER is one basis of genomic instability, a required element in cellular transformation, and one that potentially influences response to therapy. In this study, we demonstrate differences in NER capacity in eight adult mouse tissues, and place this result into the context of our previous work on mouse extraembryonic tissues, normal human tissues and sporadic early stage human breast cancer.
Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL.
Jean J
JJ
Latimer
Vongai J
VJ
Majekwana
Yashira R
YR
Pabón-Padín
Manasi R
MR
Pimpley
Stephen G
SG
Grant
D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004247:DNA / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000528:radiation effects*; D005260:Female; D014644:Genetic Variation; D042822:Genomic Instability; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009928:Organ Specificity; D046509:Tissue Culture Techniques; D014466:Ultraviolet Rays / Q000009:adverse effects
D004247:DNA; D045643:DNA Repair Enzymes