Background
BC is currently the leading cause of cancer-related death in the United States, causing 28% of all cancer deaths [1]. Although cigarette smoking is the primary risk factor, only 10–15% of heavy smokers (greater than 20 pack years) develop BC [1-3]. Antioxidant and DNA repair enzymes that provide protection from the effects of cigarette smoke are expressed in the progenitor cells for BC, normal bronchial epithelial cells (NBEC) [1]. Inherited inter-individual variation in the function of these genes plays a role in determining risk for BC [4-6]. Antioxidant enzymes protect NBEC from reactive oxygen species produced by interaction with and metabolism of xenobiotics such as pollution and cigarette smoke [4-7] as well as those produced by normal cellular metabolism. Reactive oxygen species cause many damaging reactions including denaturation of proteins, cross-linking of lipids and proteins and modification of nucleic acid bases, which can lead to cancer [7]. DNA repair enzymes repair the frequent damage to DNA caused by oxidant stress as well as other stresses, including bulky adducts derived from carcinogens in cigarette smoke [8].
We previously reported that an interactive transcript abundance index comprising antioxidant genes was lower in NBEC of BC individuals compared to non-BC individuals, suggesting that BC individuals are selected on the basis of poor antioxidant protection [9]. In that study, there was a tendency towards correlation in transcript abundance between several pairs of antioxidant or DNA repair genes in non-BC individuals, but not in BC individuals. Gene pairs included in that observation were GSTP1/GPX1, CAT/GPX3, and GPX3/SOD1.
Correlation is one typical characteristic of co-regulated genes. Another is shared transcription factor recognition sites in the regulatory regions of those genes [10]. Based on the above findings, it was hypothesized first, that there is inter-individual variation in regulation of key antioxidant and DNA repair genes by one or more transcription factors and second, that individuals with sub-optimal regulation are selected for development of BC if they smoke cigarettes. To test these hypotheses, transcription factor recognition sites common to the regulatory regions of the above correlated gene pairs were identified through in silico DNA sequence analysis, and their transcript abundance measured simultaneously with an expanded group of ten antioxidant and six DNA repair genes.