Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Finland.
Cancer Res. 2012 Nov 1;72(21):5537-46. doi: 10.1158/0008-5472.CAN-12-1474. Epub 2012 Sep 10.
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.
NRF2 会激活一些保护性基因，如硫氧还蛋白（SRXN1），以应对氧化和异生物质应激。NRF2 通路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疗耐药，从而影响患者的预后。在 452 名乳腺癌患者和 370 名对照中，对 NRF2 基因的 9 个单核苷酸多态性和 SRXN1 的 8 个单核苷酸多态性进行了基因分型。通过免疫组织化学研究了 373 例乳腺癌中 NRF2 和 SRXN1 的蛋白表达。评估了基因型、蛋白表达、临床病理变量和生存之间关联的统计学意义。在 361 例中的 237 例（66%）和 363 例中的 82 例（23%）观察到细胞质 NRF2 阳性率>25%。NRF2 rs6721961 TT 基因型与乳腺癌风险增加相关[P=0.008；OR，4.656；置信区间（CI），1.350-16.063]，T 等位基因与 NRF2 蛋白表达水平较低相关（P=0.0003；OR，2.420；CI，1.491-3.926）和 SRXN1 阴性表达相关（P=0.047；OR，1.867；CI=1.002-3.478）。NRF2 rs2886162 等位基因 A 与低 NRF2 表达相关（P=0.011；OR，1.988；CI，1.162-3.400），AA 基因型与较差的生存相关（P=0.032；HR，1.687；CI，1.047-2.748）。NRF2 rs1962142 T 等位基因与细胞质 NRF2 表达水平较低相关（P=0.036）和 SRXN1 阴性表达相关（P=0.042）。NRF2 rs2706110 AA 基因型与乳腺癌风险增加相关，SRXN1 rs6053666 C 等位基因与乳腺癌风险降低相关（P=0.011 和 0.017）。NRF2 和 SRXN1 遗传多态性与乳腺癌风险和生存相关，表明与活性氧和 NRF2 通路相关的机制参与了乳腺癌的发生和进展。
