Bladder cancer (BC) is the 4th most common cancer in men, but BC incidence is nearly 4 fold higher in men than in women across race;the underlying cause is not understood. Lack of such knowledge impedes progress in BC prevention. On the basis of our published and unpublished data, we hypothesize that hepatic UDP-glucuronosyltransferase 1A3 (UGT1A3) is a key determinant of the gender disparity in human BC development through converting androgen signal to increased urinary delivery of arylamine carcinogens to bladder tissue. Arylamines, 4-aminobiphenyl (ABP) in particular, are the main cause of human BC. We also hypothesize that sulforaphane (SF), a common dietary phytochemical, can block UGT1A3 from promoting arylamine-induced bladder carcinogenesis by boosting cytoprotective defense in the bladder. These hypotheses will be examined in four specific aims using complementary approaches of cultured cells and transgenic mouse models.
Aim 1 is to test our hypothesis that liver UGT1A3 is a key molecule that determines the gender disparity in BC development. Wild-type mice and UGT1A3 transgenic mice (liver- specific and androgen-independent expression) will be compared for ABP-induced bladder carcinogenesis. Comparison will also be made between mice with and without castration. Another carcinogen 2- acetylaminofluorene (2-AAF) will be used to rule out ABP-specific effects.
Aim 2 is to assess the impact of UGT1A3 polymorphism on its catalytic activity toward ABP and 2-AAF and on the susceptibility of bladder cells and liver cells to DNA damage induced by ABP and 2-AAF. Six single nucleotide polymorphisms occur in UGT1A3 gene. All the polymorphic variants together with the wild-type gene will be evaluated.
Aim 3 is to test our hypothesis that SF can block UGT1A3 from promoting bladder carcinogenesis by stimulating cytoprotective defense against arylamine carcinogens (ABP and 2-AAF) in the bladder, without modulating UGT1A3 in the liver. Non-interference of liver UGT1A3 may be desirable, since this enzyme may be physiologically important, such as metabolizing estrone. SF is a promising cancer-preventive agent and is selectively delivered to bladder tissue through urinary excretion. Two animal models will be used to test the hypothesis, including the UGT1A3 mouse model described above and the Tg-UGT1 mouse model (mice carry both the coding and the regulatory sequences of the human UGT1A3 gene).
Aim 4 is to confirm that UGT1A3 is transcriptionally stimulated by androgen in vivo and to elucidate the molecular mechanism by which androgen stimulates UGT1A3. This will be accomplished by using both cell models and the Tg-UGT1 mouse model. Impact: The proposed studies are expected to lead to the elucidation of the molecular basis of the gender disparity in BC and the development of new strategy for effective prevention of this disease.
It has been known for several decades that the incidence of bladder cancer is nearly 4 fold higher in men than in women across race, but the reason has remained poorly understood. Lack of such knowledge impedes progress in bladder cancer prevention, and no chemopreventive agent is currently available for prevention of bladder cancer. This application will examine the hypothesis that UGT1A3 is a key determinant of gender disparity in human bladder cancer development and also examine the hypothesis that sulforaphane, a common dietary phytochemical, can block the bladder cancer-promoting activity of UGT1A3 and inhibit bladder cancer development, and the project is expected to significantly advance the knowledge about bladder cancer and to lead to development of a new strategy for effective prevention of this disease.
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