DNA Repair and Tobacco Smoke in Bladder Carcinogenesis

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Bladder cancer (BC) is the fifth most frequent cancer found in the United States (US). Tobacco smoke (TS) is the major cause of BC in US, and tobacco smokers have a 5-fold higher BC incidence than nonsmokers. TS contains more than 60 carcinogens; however, which carcinogens are responsible for BC is not well established. Arylamines, 4-hydroxy-aminoblphenyl (ABP) in particular, are the major cause of occupation-related BC, but the amount of arylamines in TS is minute. In fact, TS contains 100,000 fold more acrolein (Acr) than ABP, and Acr is a potent and organ-specific carcinogen capable of Inducing BC in rat models. Our laboratory has a longstanding interest in studying the role of chemical carcinogen induced DNA damage and repair in tumorigenesis. We recently made three important findings regarding Acr: (1) Acr damages DNA by forming Acr-DNA adducts that are mutagenic; (ii) Acr inhibits DNA repair by modifying and accelerating autophagy-mediated degradation of the modified DNA repair proteins; and (iii) Acr-DNA adducts are poorly repaired in human cells. We propose that Acr Is a major bladder carcinogen and its carcinogenicity Is via these three detrimental effects (Hypothesis 1). Most BC can be classified as either noninvasive (N-lnv) or invasive (Inv); while N-lnv-BC often bear mutations in codon 12 ofthe H-RAS (<20%) and codons 248, 249, 372 and 652 ofthe FGFRS gene (80%), Inv-BC mainly carry mutations in the p53 (30-60%) and RB genes. We hypothesize that these mutation hotspots in BC are Acr preferential binding sites in bladder urothelial cells (Hypothesis 2). We found that DNA damage induces much higher mutations in Inv-BC cells than in N-lnv-BC cells and that N-lnv-BC cells have a much higher DNA damage repair capacity than Inv-BC cells. We also recently found that p63 gene is highly expressed in N-lnv-BC but not in Inv-BC cells, and that introduction of p63 gene elevates DNA repair capacity in Inv-BC cells. These results lead us to hypothesize that H- RAS/FGFR3 mutation-activation enhances DNA repair capacity via activation of p63 and that p53 mutations reduce DNA repair capacity via down regulation of p63 (Hypothesis 3). We will test these hypotheses in cultured human urothelial cells, human bladder tumor tissue samples and transgenic mouse models to understand the relationship between DNA repair capacity and divergent pathways of bladder cancer.