Increased NOS2 predicts poor survival in estrogen receptor-negative breast cancer patients
Increased NOS2 predicts poor survival in estrogen receptor-negative breast cancer patients
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DOI：
10.1172/jci42059
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发表时间：
2010-11-01
影响因子：
15.9
通讯作者：
Ambs, Stefan
中科院分区：
文献类型：
--
作者：
Glynn, Sharon A.;Boersma, Brenda J.;Ambs, Stefan
诱导型一氧化氮合酶（NOS 2）参与伤口愈合、血管生成和癌变。NOS 2上调和一氧化氮（NO）产生增加影响细胞的氧化还原状态，并可诱导蛋白质，脂质和DNA修饰。为了研究NOS 2水平是否影响乳腺癌患者的生存率，我们检测了248例乳腺肿瘤中NOS 2的表达及其与肿瘤标志物和生存率的相关性。在多变量生存分析中，NOS 2增加预测雌激素受体α阴性（ER阴性）肿瘤妇女的生存率较低。从ER阴性的高NOS 2肿瘤中显微切割的肿瘤上皮细胞具有增加的IL-8和预后不良的基底样乳腺癌的基因表达特征。在细胞培养中，NO仅诱导ER阴性乳腺癌细胞中选定的标记基因。ER阴性细胞中的ER转基因表达抑制了NO诱导的干细胞标志物CD 44和其他由特征基因编码的蛋白质的上调，但不抑制IL-8的上调。暴露于NO也增强细胞运动和ER阴性细胞的侵袭。最后，通路分析将肿瘤NOS 2基因签名与c-Myc激活联系起来。因此，NOS 2与ER阴性患者的基底样转录模式和较差的存活率相关。
Inducible nitric oxide synthase (NOS2) is involved in wound healing, angiogenesis, and carcinogenesis. NOS2 upregulation and increased nitric oxide (NO) production affect the redox state of cells and can induce protein, lipid, and DNA modifications. To investigate whether NOS2 levels influence survival of breast cancer patients, we examined NOS2 expression and its association with tumor markers and survival in 248 breast tumors. In multivariable survival analysis, increased NOS2 predicted inferior survival in women with estrogen receptor alpha-negative (ER-negative) tumors. Microdissected tumor epithelium from ER-negative tumors with high NOS2 had increased IL-8 and a gene expression signature characteristic of basal-like breast cancer with poor prognosis. In cell culture, NO only induced selected signature genes in ER-negative breast cancer cells. ER transgene expression in ER-negative cells inhibited NO-induced upregulation of the stem cell marker CD44 and other proteins encoded by signature genes, but not of IL-8. Exposure to NO also enhanced cell motility and invasion of ER-negative cells. Last, pathway analysis linked the tumor NOS2 gene signature to c-Myc activation. Thus, NOS2 is associated with a basal-like transcription pattern and poor survival of ER-negative patients.