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 共查询到20条相似文献,搜索用时 15 毫秒
1.
Gene expression profiling predicts clinical outcome of breast cancer   总被引:243,自引:0,他引:243  
Breast cancer patients with the same stage of disease can have markedly different treatment responses and overall outcome. The strongest predictors for metastases (for example, lymph node status and histological grade) fail to classify accurately breast tumours according to their clinical behaviour. Chemotherapy or hormonal therapy reduces the risk of distant metastases by approximately one-third; however, 70-80% of patients receiving this treatment would have survived without it. None of the signatures of breast cancer gene expression reported to date allow for patient-tailored therapy strategies. Here we used DNA microarray analysis on primary breast tumours of 117 young patients, and applied supervised classification to identify a gene expression signature strongly predictive of a short interval to distant metastases ('poor prognosis' signature) in patients without tumour cells in local lymph nodes at diagnosis (lymph node negative). In addition, we established a signature that identifies tumours of BRCA1 carriers. The poor prognosis signature consists of genes regulating cell cycle, invasion, metastasis and angiogenesis. This gene expression profile will outperform all currently used clinical parameters in predicting disease outcome. Our findings provide a strategy to select patients who would benefit from adjuvant therapy.  相似文献   

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The human oestrogen receptor functions in yeast   总被引:66,自引:0,他引:66  
D Metzger  J H White  P Chambon 《Nature》1988,334(6177):31-36
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Wang YC  Khan Z  Kaschube M  Wieschaus EF 《Nature》2012,484(7394):390-393
During tissue morphogenesis, simple epithelial sheets undergo folding to form complex structures. The prevailing model underlying epithelial folding involves cell shape changes driven by myosin-dependent apical constriction. Here we describe an alternative mechanism that requires differential positioning of adherens junctions controlled by modulation of epithelial apical-basal polarity. Using live embryo imaging, we show that before the initiation of dorsal transverse folds during Drosophila gastrulation, adherens junctions shift basally in the initiating cells, but maintain their original subapical positioning in the neighbouring cells. Junctional positioning in the dorsal epithelium depends on the polarity proteins Bazooka and Par-1. In particular, the basal shift that occurs in the initiating cells is associated with a progressive decrease in Par-1 levels. We show that uniform reduction of the activity of Bazooka or Par-1 results in uniform apical or lateral positioning of junctions and in each case dorsal fold initiation is abolished. In addition, an increase in the Bazooka/Par-1 ratio causes formation of ectopic dorsal folds. The basal shift of junctions not only alters the apical shape of the initiating cells, but also forces the lateral membrane of the adjacent cells to bend towards the initiating cells, thereby facilitating tissue deformation. Our data thus establish a direct link between modification of epithelial polarity and initiation of epithelial folding.  相似文献   

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Oestrogen receptor binding is not restricted to target nuclei   总被引:1,自引:0,他引:1  
G C Chamness  A W Jennings  W L McGuire 《Nature》1973,241(5390):458-460
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Pituitary adenylate cyclase-activating polypeptide (PACAP) is known to broadly regulate the cellular stress response. In contrast, it is unclear if the PACAP-PAC1 receptor pathway has a role in human psychological stress responses, such as post-traumatic stress disorder (PTSD). Here we find, in heavily traumatized subjects, a sex-specific association of PACAP blood levels with fear physiology, PTSD diagnosis and symptoms in females. We examined 44 single nucleotide polymorphisms (SNPs) spanning the PACAP (encoded by ADCYAP1) and PAC1 (encoded by ADCYAP1R1) genes, demonstrating a sex-specific association with PTSD. A single SNP in a putative oestrogen response element within ADCYAP1R1, rs2267735, predicts PTSD diagnosis and symptoms in females only. This SNP also associates with fear discrimination and with ADCYAP1R1 messenger RNA expression in human brain. Methylation of ADCYAP1R1 in peripheral blood is also associated with PTSD. Complementing these human data, ADCYAP1R1 mRNA is induced with fear conditioning or oestrogen replacement in rodent models. These data suggest that perturbations in the PACAP-PAC1 pathway are involved in abnormal stress responses underlying PTSD. These sex-specific effects may occur via oestrogen regulation of ADCYAP1R1. PACAP levels and ADCYAP1R1 SNPs may serve as useful biomarkers to further our mechanistic understanding of PTSD.  相似文献   

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Ben-Chaim Y  Chanda B  Dascal N  Bezanilla F  Parnas I  Parnas H 《Nature》2006,444(7115):106-109
Activation by agonist binding of G-protein-coupled receptors (GPCRs) controls most signal transduction processes. Although these receptors span the cell membrane, they are not considered to be voltage sensitive. Recently it was shown that both the activity of GPCRs and their affinity towards agonists are regulated by membrane potential. However, it remains unclear whether GPCRs intrinsically respond to changes in membrane potential. Here we show that two prototypical GPCRs, the m2 and m1 muscarinic receptors (m2R and m1R), display charge-movement-associated currents analogous to 'gating currents' of voltage-gated channels. The gating charge-voltage relationship of m2R correlates well with the voltage dependence of the affinity of the receptor for acetylcholine. The loop that couples m2R and m1R to their G protein has a crucial function in coupling voltage sensing to agonist-binding affinity. Our data strongly indicate that GPCRs serve as sensors for both transmembrane potential and external chemical signals.  相似文献   

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Most successful vaccines elicit neutralizing antibodies and this property is a high priority when developing an HIV vaccine. Indeed, passively administered neutralizing antibodies have been shown to protect against HIV challenge in some of the best available animal models. For example, antibodies given intravenously can protect macaques against intravenous or mucosal SHIV (an HIV/SIV chimaera) challenge and topically applied antibodies can protect macaques against vaginal SHIV challenge. However, the mechanism(s) by which neutralizing antibodies afford protection against HIV is not understood and, in particular, the role of antibody Fc-mediated effector functions is unclear. Here we report that there is a dramatic decrease in the ability of a broadly neutralizing antibody to protect macaques against SHIV challenge when Fc receptor and complement-binding activities are engineered out of the antibody. No loss of antibody protective activity is associated with the elimination of complement binding alone. Our in vivo results are consistent with in vitro assays indicating that interaction of Fc-receptor-bearing effector cells with antibody-complexed infected cells is important in reducing virus yield from infected cells. Overall, the data suggest the potential importance of activity against both infected cells and free virus for effective protection against HIV.  相似文献   

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为了提高乳腺癌患者的生存率,改善病人的临床治疗效果,从分子机制上研究了乳腺癌的致病基因。首先对113个正常组织和1 109个癌症组织的表达量进行差异分析,然后对差异表达的基因采用条件联合分析方式对互补基因进行分组,并用逐步Cox回归挑选出一组基因拟合预后模型。研究结果显示:VWCE,SPDYC,CRYBG3,DEFB1,SEL1L2,NMNAT2 6个基因对患者生存率是有害的,AMZ1,GJB2,CXCL2,ALDOC 4个基因对患者生存率是有利的,最终确定10个基因的预后模型能够显著地将样本分为高风险组和低风险组,并且对乳腺癌患者5年和10年的生存率进行了预测,依赖时间的AUC值均可达0.7以上。所提方法能够利用基因与基因之间的关联性,很好地对高维数据进行降维,消除基因与基因之间的共线性问题,10个基因的预后模型可以对患者的临床预测提供帮助。  相似文献   

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Cancer cells adapt their metabolic processes to drive macromolecular biosynthesis for rapid cell growth and proliferation. RNA interference (RNAi)-based loss-of-function screening has proven powerful for the identification of new and interesting cancer targets, and recent studies have used this technology in vivo to identify novel tumour suppressor genes. Here we developed a method for identifying novel cancer targets via negative-selection RNAi screening using a human breast cancer xenograft model at an orthotopic site in the mouse. Using this method, we screened a set of metabolic genes associated with aggressive breast cancer and stemness to identify those required for in vivo tumorigenesis. Among the genes identified, phosphoglycerate dehydrogenase (PHGDH) is in a genomic region of recurrent copy number gain in breast cancer and PHGDH protein levels are elevated in 70% of oestrogen receptor (ER)-negative breast cancers. PHGDH catalyses the first step in the serine biosynthesis pathway, and breast cancer cells with high PHGDH expression have increased serine synthesis flux. Suppression of PHGDH in cell lines with elevated PHGDH expression, but not in those without, causes a strong decrease in cell proliferation and a reduction in serine synthesis. We find that PHGDH suppression does not affect intracellular serine levels, but causes a drop in the levels of α-ketoglutarate, another output of the pathway and a tricarboxylic acid (TCA) cycle intermediate. In cells with high PHGDH expression, the serine synthesis pathway contributes approximately 50% of the total anaplerotic flux of glutamine into the TCA cycle. These results reveal that certain breast cancers are dependent upon increased serine pathway flux caused by PHGDH overexpression and demonstrate the utility of in vivo negative-selection RNAi screens for finding potential anticancer targets.  相似文献   

16.
The excision repair cross-complementing group 2 (ERCC2) gene encodes a DNA repair protein, which is absolutely necessary in nucleotide excision repair. A polymorphism in codon 751 that induces a Lys→Gln substitution has been suggested to reduce the DNA repair capacity. Therefore, we conducted a matched case-control study to investigate the role of ERCC2 Lys751Gln polymorphism in the development of lung cancer in the Chinese population. The genotype of ERCC2 gene was analyzed by di-allele-specific-amplification with artificially modified primers (diASA-AMP) in 200 original lung cancer cases and 200 controls. The results showed that carriers of Lys/Gln and Gln/Gln genotypes had a 3.32-fold higher risk of lung cancer compared with carriers of Lys/Lys genotype. Furthermore, the mutant genotype of 751Gln allele was found to be associated with an increased risk in both lung squamous cell carcinoma and lung adenocarcinoma. However, no significant interaction between 751Gln variants and smoking was observed after stratifying according to the smoking status in this study. The results suggest that the Lys751Gln polymorphism in ERCC2 gene is a potential biomarker for susceptibility of lung cancer in the Chinese population.  相似文献   

17.
The excision repair cross-complementing group 2(ERCC2)gene encodes a DNA repair protein,which is absolutely necessary in nucleotide excision repair.A polymorphism in codon 751 that induces a Lys→Gln substitution has been suggested to reduce the DNA repair capacity.Therefore,we conducted a matched case-control study to investigate the role of ERCC2 Lys751Gln polymor- phism in the development of lung cancer in the Chinese population.The genotype of ERCC2 gene was analyzed by di-allele-specific-amplifi- cation with artificially modified primers(diASA-AMP)in 200 original lung cancer cases and 200 controls.The results showed that carriers of Lys/Gln and Gln/Gln genotypes had a 3.32-fold higher risk of lung cancer compared with carriers of Lys/Lys genotype.Furthermore, the mutant genotypa of 751Gln allele was found to be associated with an increased risk in both lung squamous cell carcinoma and lung ade- nocarcinoma.However,no significant interaction between 751Gln variants and smoking was observed after stratifying according to the smoking status in this study.The results suggest that the Lys751Gln polymorphism in ERCC2 gene is a potential biomarker for suscepti- bility of lung cancer in the Chinese population.  相似文献   

18.
目的 探讨我国青年女性乳腺癌的临床和病理特点.方法 全面收集国内关于青年女性乳腺的临床研究论文.青年女性(≤35岁)乳腺癌患者为研究组,>35岁以上女性乳腺癌患者为对照组.结果 共检索符合纳入标准及排除标准的论文8篇,包括4881例病例,研究组发病至就诊时间明显长于对照组.采用随机效应模型进行meta分析,两组的TNM分期、腋窝淋巴结转移、免疫组化有显著差异,病理分型、5年生存率无明显差异.结论 青年女性乳腺癌虽然更多发生腋窝淋巴结转移,TNM分期较晚,ER阳性率低,但经积极治疗,可能取得与中老年女性乳腺癌一样的效果,年龄不是影响预后的独立因素.  相似文献   

19.
目的:检测血清miR-21在乳腺癌中的表达差异,为进一步阐明miR-21在家族性和三阴性乳腺癌发病机制中的作用.方法:收集健康女性体检者、具有患乳腺癌高风险者、不同种类乳腺癌患者的血清.以线虫miR-39为外参,通过实时荧光定量PCR检测77份血清中miR-21的表达水平.结果:家族性乳腺癌组、三阴性乳腺癌组和乳腺癌高风险组血清miR-21水平显著高于正常对照组、其他乳腺癌组(P0.01).血清miR-21的表达水平与淋巴结转移、Ki67高表达有关(P0.01).结果显示血清miR-21表达量在家族性和三阴性乳腺癌中升高,且与淋巴结转移和Ki67表达有关.结论:血清miR-21与三阴性、家族性乳腺癌的发生有紧密联系,其表达增高与乳腺癌的遗传性、恶性程度及预后判断有关.  相似文献   

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目的探讨我国青年女性乳腺癌的临床和病理特点。方法全面收集国内关于青年女性乳腺的临床研究论文。青年女性(≤35岁)乳腺癌患者为研究组,>35岁以上女性乳腺癌患者为对照组。结果共检索符合纳入标准及排除标准的论文8篇,包括4881例病例,研究组发病至就诊时间明显长于对照组。采用随机效应模型进行meta分析,两组的TNM分期、腋窝淋巴结转移、免疫组化有显著差异,病理分型、5年生存率无明显差异。结论青年女性乳腺癌虽然更多发生腋窝淋巴结转移,TNM分期较晚,ER阳性率低,但经积极治疗,可能取得与中老年女性乳腺癌一样的效果,年龄不是影响预后的独立因素。  相似文献   

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