Genetic polymorphisms in uridine diphospho-glucuronosyltransferase 1A1 and association with breast cancer among African Americans.
Genetic polymorphisms in uridine diphospho-glucuronosyltransferase 1A1 and association with breast cancer among African Americans.
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发表时间：
2000-02
期刊：
影响因子：
11.2
通讯作者：
Chantal Guillemette;R. Millikan;Beth Newman;David E. Housman
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作者：
Chantal Guillemette;R. Millikan;Beth Newman;David E. Housman
我们研究了 UDP-葡萄糖醛酸基转移酶 (UGT) 1A1 位点的体质遗传变异在乳腺癌易感性中的作用。 UGT1A1 酶是参与雌二醇葡萄糖醛酸化的主要 UGT。迄今为止，在非裔美国人群体中已描述了四个 UGT1A1 变异等位基因，其特征是非典型 TATA 框区域中 TA 重复次数从 5 到 8 个变化。对乳腺和肝细胞转录活性的功能分析表明，报告基因的转录激活与重复次数成反比。逆转录PCR分析证实了肝癌细胞系HepG2中人类肝脏中UGT1A1的表达，并提供了乳腺癌组织中UGT1A1表达的证据，其中在测试的12个乳腺癌细胞系中的11个中观察到阳性信号。这项基于人群的病例对照研究涉及 200 名患有乳腺癌的女性和 200 名非洲血统的女性对照。我们假设乳腺癌病例中含有低活性等位基因的基因型的患病率可能高于对照（等位基因在 TATA 盒的 A(TA)nTAA 基序中呈现七个和八个重复）。将具有 7 种和 8 种等位基因基因型的女性与 5/5、5/6 和 6/6 基因型的女性进行比较，乳腺癌的年龄调整优势比 (OR) 为 1.8 [95% 置信区间 (CI)，1.0-3.1；95% 置信区间 (CI)，1.0-3.1；绝经前女性中 P = 0.06]，绝经后女性中 P = 0.06（95% CI，0.5-1.7；P = 0.9）。观察到绝经前女性患浸润性乳腺癌的风险增加 1.8 倍，高度提示 UGT 基因型和激素之间可能存在相互作用。其他分析表明 UGT1A1 基因型与雌激素受体 (ER) 阴性乳腺癌的关联性更强。在绝经前女性中，ER-乳腺癌（OR，2.1；95% CI，1.0-4.2；P = 0.04）的相关性比 ER+ 乳腺癌（OR，1.3；95% CI，0.6-3.0；P = 0.5）更强。在使用口服避孕药的女性中，OR 稍强，而在绝经后女性中，无论她们是否接受激素替代疗法，这种关联仍然为零。我们目前的研究结果表明，需要进一步研究来阐明 UGT1A1 在乳腺癌风险中的作用。
We examined the role of constitutional genetic variation at the UDP-glucuronosyltransferase (UGT) 1A1 locus in breast cancer susceptibility. The UGT1A1 enzyme is a major UGT involved in estradiol glucuronidation. To date, four UGT1A1 variant alleles characterized by a variation in the number of TA from five through eight repeats in the atypical TATA box region have been described in the African-American population. Functional analyses of the transcriptional activity in breast and liver cells revealed that the transcription activation of a reporter gene is inversely correlated with the number of repeats. Reverse transcription-PCR analysis confirmed the expression of UGT1A1 in human liver in the hepatocarcinoma cell line HepG2 and provided evidence of the expression of UGT1A1 in breast cancer tissue, where a positive signal was observed in 11 of 12 breast cancer cell lines tested. The population-based case-control study involved 200 women with breast cancer and 200 female controls of African ancestry. We postulated that breast cancer cases might have a higher prevalence of low activity allele-containing genotypes than controls (alleles presenting seven and eight repeats in the A(TA)nTAA motif of the TATA box). The age-adjusted odds ratio (OR) for breast cancer comparing women with seven and eight allele-containing genotypes versus 5/5, 5/6, and 6/6 genotypes was 1.8 [95% confidence interval (CI), 1.0-3.1; P = 0.06] in premenopausal women and 1.0 (95% CI, 0.5-1.7; P = 0.9) in postmenopausal women. The observed 1.8-fold elevated risk in premenopausal women with invasive breast cancer is highly suggestive of a possible interaction between UGT genotype and hormones. Additional analyses suggested a stronger association of UGT1A1 genotype with estrogen receptor (ER)-negative breast cancer. Among premenopausal women, the association was stronger for ER- breast cancer (OR, 2.1; 95% CI, 1.0-4.2; P = 0.04) than ER+ breast cancer (OR, 1.3; 95% CI, 0.6-3.0; P = 0.5). The OR was slightly stronger among women who used oral contraceptives, and the association remained null in postmenopausal women, regardless of whether they took hormone replacement therapy. Our current findings suggest that further investigations are warranted to elucidate the role of UGT1A1 in breast cancer risk.