Shatalova Ekaterina G, Walther Susan E, Favorova Olga O, Rebbeck Timothy R, Blanchard Rebecca L
Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
Breast Cancer Res. 2005;7(6):R909-21. doi: 10.1186/bcr1318. Epub 2005 Sep 21.
Estrogens are important in breast cancer development. SULT1A1 and UGT1A1 catalyze estrogen metabolism and are polymorphic. The SULT1A12 protein exhibits low activity, and a TA repeat within the UGT1A1 promoter alters the level of expression of the protein. We hypothesized that the SULT1A12 allozyme has decreased capacity to sulfate estrogens, that the SULT1A1*2 allele conferred increased capacity of cells to proliferate in response to estrogens, and that individuals with the variant SULT1A1 and UGT1A1 genotypes exhibited different breast tumor characteristics.
The capacity for SULT1A12 to sulfate 17beta-estradiol and the capacity for cells expressing SULT1A11 or SULT1A1*2 to proliferate in response to 17beta-estradiol was evaluated. A case-series study was performed in a total of 210 women with incident breast cancer, including 177 Caucasians, 25 African-Americans and eight women of other ethnic background. The SULT1A1 and UGT1A1 genotypes were determined and a logistic regression model was used to analyze genotype-phenotype associations.
We determined that the SULT1A1*1/*1 high-activity genotype was associated with tumor size <or=2 cm (odds ratio = 2.63, 95% confidence interval = 1.25-5.56, P = 0.02). Individuals with low-activity UGT1A1 genotypes (UGT1A1*28/*28 or UGT1A1*28/*34) were more likely to have an age at diagnosis >or=60 years (odds ratio = 3.70, 95% confidence interval = 1.33-10.00, P = 0.01). Individuals with both SULT1A1 and UGT1A1 high-activity genotypes had low tumor grade (odds ratio = 2.56, 95% confidence interval = 1.04-6.25, P = 0.05). Upon stratification by estrogen receptor status, significant associations were observed predominantly in estrogen receptor-negative tumors.
The data suggest that genetic variation in SULT1A1 and UGT1A1 may influence breast cancer characteristics and might be important for breast cancer prognosis.
雌激素在乳腺癌发展过程中起着重要作用。SULT1A1和UGT1A1催化雌激素代谢且具有多态性。SULT1A12蛋白活性较低，UGT1A1启动子内的TA重复序列会改变该蛋白的表达水平。我们推测，SULT1A12同工酶硫酸化雌激素的能力下降，SULT1A1*2等位基因赋予细胞对雌激素反应的增殖能力增强，且具有SULT1A1和UGT1A1基因变异型的个体表现出不同的乳腺肿瘤特征。
评估SULT1A12硫酸化17β-雌二醇的能力以及表达SULT1A11或SULT1A1*2的细胞对17β-雌二醇反应的增殖能力。对总共210例新发乳腺癌女性进行了一项病例系列研究，其中包括177名白种人、25名非裔美国人和8名其他种族背景的女性。确定了SULT1A1和UGT1A1基因型，并使用逻辑回归模型分析基因型与表型的关联。
我们确定SULT1A1*1/1高活性基因型与肿瘤大小≤2 cm相关（比值比 = 2.63，95%置信区间 = 1.25 - 5.56，P = 0.02）。UGT1A1低活性基因型（UGT1A128/28或UGT1A128/*34）的个体更有可能诊断时年龄≥60岁（比值比 = 3.70，95%置信区间 = 1.33 - 10.00，P = 0.01）。同时具有SULT1A1和UGT1A1高活性基因型的个体肿瘤分级较低（比值比 = 2.56，95%置信区间 = 1.04 - 6.25，P = 0.05）。按雌激素受体状态分层后，主要在雌激素受体阴性肿瘤中观察到显著关联。
数据表明，SULT1A1和UGT1A1的基因变异可能影响乳腺癌特征，对乳腺癌预后可能很重要。
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