Genetic Polymorphisms and Protein Expression of NRF2 and Sulfiredoxin Predict Survival Outcomes in Breast Cancer
Genetic Polymorphisms and Protein Expression of NRF2 and Sulfiredoxin Predict Survival Outcomes in Breast Cancer
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DOI：
10.1158/0008-5472.can-12-1474
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发表时间：
2012-11-01
期刊：
影响因子：
11.2
通讯作者：
Soini, Ylermi
中科院分区：
文献类型：
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作者：
Hartikainen, Jaana M.;Tengstroem, Maria;Soini, Ylermi
NRF2激活几个保护性基因，如硫氧还蛋白(SRXN1)，作为对氧化和异物应激的反应。NRF2途径的缺陷可能会增加癌症的易感性。在肿瘤细胞中，NRF2的激活可能导致化疗和放射耐药，从而影响患者的预后。对452例乳腺癌患者和370例正常对照进行了NRF2基因9个单核苷酸多态和SRXN1 8个单核苷酸多态的基因分型。应用免疫组织化学方法检测了373例乳腺癌组织中NRF2和SRXN1蛋白的表达。评估了基因型别、蛋白表达、临床病理变量和存活率之间的统计学意义。细胞质NRF2高表达237例(66%)，SRXN1高表达82例(23%)。T等位基因与NRF2蛋白低表达(P=0.0003；OR，2.420；CI，1.491~3.926)和SRXN1阴性表达(P=0.047；OR，1.867；CI=1.002~3.478)相关。NRF2rs2886162等位基因A与NRF2低表达相关(P=0.011；OR，1.988；CI，1.162~3.400)，AA等位基因与预后相关(P=0.032；HR，1.687；CI，1.047~2.748)。NRF2rs1962142T等位基因与NRF2胞浆低表达(P=0.036)和硫氧还蛋白阴性表达(P=0.042)相关。NRF2rs2706110AA基因型与乳腺癌风险增加相关，SRXN1rs6053666C等位基因与乳腺癌风险降低相关(P=0.011和0.017)。NRF2和SRXN1基因多态性与乳腺癌的风险和生存期有关，提示与活性氧和NRF2通路相关的机制参与了乳腺癌的发生和发展。癌症资源；72(21)；5537-46。(C)2012年AACR。
NRF2 activates several protective genes, such as sulfiredoxin (SRXN1), as a response to oxidative and xenobiotic stress. Defects in NRF2 pathway may increase cancer susceptibility. In tumor cells, activation of NRF2 may lead to chemo-and radioresistance and thus affect patient outcome. Nine single-nucleotide polymorphisms on NRF2 gene and eight on SRXN1 were genotyped in 452 patients with breast cancer and 370 controls. Protein expression of NRF2 and SRXN1 was studied in 373 breast carcinomas by immunohistochemistry. Statistical significance of the associations between genotypes, protein expression, clinicopathologic variables, and survival was assessed. A high level (>25%) of cytoplasmic NRF2 positivity was observed in 237 of 361 (66%) and SRXN1 positivity was observed in 82 of 363 (23%) cases. The NRF2 rs6721961 genotype TT was associated with increased risk of breast cancer [P = 0.008; OR, 4.656; confidence interval (CI), 1.350-16.063] and the T allele was associated with a low extent of NRF2 protein expression (P = 0.0003; OR, 2.420; CI, 1.491-3.926) and negative SRXN1 expression (P = 0.047; OR, 1.867; CI = 1.002-3.478). The NRF2 rs2886162 allele A was associated with low NRF2 expression (P = 0.011; OR, 1.988; CI, 1.162-3.400) and the AA genotype was associated with a worse survival (P = 0.032; HR, 1.687; CI, 1.047-2.748). The NRF2 rs1962142 T allele was associated with a low level of cytoplasmic NRF2 expression (P = 0.036) and negative sulfiredoxin expression (P = 0.042). The NRF2 rs2706110 AA genotype was associated with an increased risk of breast cancer, and the SRXN1 rs6053666 C allele was associated with a decrease in breast cancer risk (P = 0.011 and 0.017). NRF2 and SRXN1 genetic polymorphisms are associated with breast cancer risk and survival, implicating that mechanisms associated with reactive oxygen species and NRF2 pathway are involved in breast cancer initiation and progression. Cancer Res; 72(21); 5537-46. (C)2012 AACR.