| Co-Investigator(Kenkyū-buntansha) |
NISHIO Hisahide Kobe University, Graduate School of Medicine, Professor, 大学院医学系研究科, 教授 (80189258)
AYAKI Hitoshi Kobe University, Graduate School of Medicine, Associate Professor, 大学院医学系研究科, 助教授 (80222701)
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| Budget Amount *help |
¥9,500,000 (Direct Cost: ¥9,500,000)
Fiscal Year 2006: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 2005: ¥5,300,000 (Direct Cost: ¥5,300,000)
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| Research Abstract |
UGT1A1 is a glucuronidation enzyme for estrogen and bilirubin. Some of the mutations on UGT1A1 gene decreased the activity of UGT1A1 enzyme, and may increase the concentration of estrogen in the body. In this study, we investigated distribution of G71R and-3279T>G mutations on UGT1A1 gene in Japanese and Korean breast cancer patients and controls, and discussed about the influence of these mutations on the onset of breast cancer.
1. We applied DHPLC method for G71R mutation detection. In Japanese control (n=81) and breast cancer patients (n=95), mutated allele frequencies were 0.15 and 0.11, respectively. The data did not differ significantly. In Korean control (n=100) and breast cancer patients (n=88), mutated allele frequencies were 0.17 and 0.02, respectively. The allele frequency was significantly lower in breast cancer patients. Thus, the presence of the G71R mutation is unlikely to contribute to onset of breast cancer.
2. COP-PCR was applied to detect-3279T>G mutation. In Japanese
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control (n=65) and breast cancer patients (n=88), mutated allele frequency were 0.34 and 0.48, respectively, which was significantly different. These data suggested the possibility that-3279T>G mutation may affect breast cancer onset in Japanese. In case of Korean control (n=67) and breast cancer patients (n=48), mutated allele frequency did not differ significantly (0.17 and 0.03, respectively). The allele frequency between Japanese and Korean control showed significant difference, which suggested the effect of genetic differences between two ethnic groups on the onset of breast cancer.
3. In order to assay the activities of mutated UGT1A1 enzymes, we constructed recombinant expression clones for G71R, F83L, I322V and G493R mutants.. The activities toward 17β-estradiol (E2) were measured using LC/MS/MS. The UGT1A1 activities of G71R, F83L, I322V and G493R mutants were 24, 30, 18 and 0.6% of the normal UGT1A1 activity, respectively. The mutations remarkably reduced the activity of UGT1A1. Less
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