EB病毒基因BARF1在鼻咽癌细胞中的表达及意义

目的：探讨EB(Epstein—Barr)病毒新基因BARF1(BamHI A rightward open reading frame1)在人鼻咽癌组织中的表达及意义，为深入阐明EB病毒致癌机制提供实验依据。方法：提取RNA后，采用RT—PCR方法扩增标本中的EBNA1(EB virus associated nuclear antigen 1)和BARF1 mRNA，PCR产物经2％琼脂糖凝胶电泳观察并照相。结果：11例RNA合格的标本均表达EBNA1，提示病例均为EB病毒阳性病例；其中9例表达BARF1，占82％：而且9例中的7例为强阳性。结论：EB病毒新基因BARF1 mRNA在鼻咽癌细胞中高表达，这提示除了已经明确的潜伏性膜蛋白1(LMP1)以外，BARF1可能在鼻咽癌细胞恶性增殖中发挥重要作用，具体机制有待深入研究。     

The Human Immunodeficiency Virus Type-1 (HIV-1) Tat Protein and Bcl-2 Gene Expression

Tat protein of human immunodeficiency virus type-1 (HIV-1) plays a central role in viral replication and shows pleiotropic effects on the survival and growth of different cell types. Remarkably, Tat represents the first example of a viral protein, that can also be actively secreted by infected cells and shows a cytokine-like activity on both HIV-1 infected and uninfected cells. We previously reported that the stable expression of tat cDNA rescues Jurkat cell lines from apoptosis induced by a variety of stimuli, such as serum withdrawal, engagement of fas antigen or even a productive infection with HIV-1. These findings suggested that Tat was able to modulate the expression of one or more gene(s) relevant for the control of cell survival/death. Consistently, Jurkat cells stably transfected with tat show an upregulated expression of bcl-2. It is still unsettled whether Tat affects cell survival and bcl-2 expression directly or indirectly, modulating the expression of other cellular genes involved in the control of cell survival or encoding for cytokines. Blocking experiments performed with anti-Tat neutralizing antibodies revealed that Tat increases bcl-2 expression and prevent lymphoid T cells from apoptosis by acting, at least in part, through an autocrine/paracrine loop.

While high (nM-μM) concentrations of extracellular Tat display a cytotoxic activity on the antigen-mediated induction of T cell proliferation, low (pM) concentrations of Tat were able to protect both Jurkat cells and primary peripheral blood mononuclear cells from apoptosis. Significantly, pM concentrations of Tat were detected in the sera of some HIV-1 infected individuals as well as in the culture supernatant of HIV-1 infected cells, raising the possibility that these levels of Tat protein may be present physiologically in vivo. The potential relevance of Tat-mediated upregulation of bcl-2 for the pathogenesis of HIV-1 disease is discussed.     

EBV-LMP1对鼻咽癌细胞系CNE1细胞凋亡的影响

背景与目的:已证实EB病毒编码的潜伏膜蛋白1(latentmembraneprotein,LMP1)具有转化致瘤作用,在鼻咽癌的发生发展中起重要作用。LMP1的转化致瘤作用可能与细胞凋亡有关,本实验目的是观察EBV-LMP1对鼻咽癌细胞系CNE1细胞凋亡的影响,探索LMP1在鼻咽癌发生发展中的可能机制。方法:用电转染的方法将带有绿色荧光蛋白GFP报道系统的EB病毒LMP1基因真核表达质粒导入CNE1,用荧光显微镜检测报道基因GFP的表达情况;用免疫组化法及Westernblot法检测目的基因LMP1的表达情况;用流式细胞仪、荧光染色及DNA片段分析等方法检测在有地塞米松磷酸钠或无血清饥饿诱导的情况下LMP1对CNE1细胞凋亡的影响。结果:CNE1G细胞(转染空载质粒PAT-GFP的CNE1细胞)及CNE1GL(转染目的基因质粒PAT-GFP-LMP1的CNE1细胞)有绿色荧光蛋白表达,CNE1细胞(未经转染的CNE1细胞)无绿色荧光蛋白表达;CNE1GL细胞LMP1呈阳性表达,而CNE1及CNE1G细胞均为阴性。CNE1、CNE1G及CNE1GL3组细胞分别用地塞米松磷酸钠或无血清1640培养液处理后均有凋亡出现,且两种诱导方法均能使CNE1GL组细胞的凋亡指数(apoptosisindex,AI)较CNE1及CNE1G组明显增高(P<0.05),而CNE1与CNE1G组的凋亡指数无明显差别。3组细胞常规培养下则无凋亡出现。结论:LMP1基因成功导入CNE1细胞     

Deregulated Expression of Cry1 and Cry2 in Human Gliomas

Growing evidence shows that deregulation of the circadian clock plays an important role in the developmentof malignant tumors, including gliomas. However, the molecular mechanisms of gene chnages controllingcircadian rhythm in glioma cells have not been explored. Using real time polymerase chain reaction andimmunohistochemistry techniques, we examined the expression of two important clock genes, cry1 and cry2,in 69 gliomas. In this study, out of 69 gliomas, 38 were cry1-positive, and 51 were cry2-positive. The expressionlevels of cry1 and cry2 in glioma cells were significantly different from the surrounding non-glioma cells (P<0.01).The difference in the expression rate of cry1 and cry 2 in high-grade (grade III and IV) and low-grade (grade 1and II) gliomas was non-significant (P>0.05) but there was a difference in the intensity of immunoactivity forcry 2 between high-grade gliomas and low-grade gliomas (r=-0.384, P=0.021). In this study, we found that theexpression of cry1 and cry2 in glioma cells was much lower than in the surrounding non-glioma cells. Therefore,we suggest that disturbances in cry1 and cry2 expression may result in the disruption of the control of normalcircadian rhythm, thus benefiting the survival of glioma cells. Differential expression of circadian clock genesin glioma and non-glioma cells may provide a molecular basis for the chemotherapy of gliomas.     

错配修复基因hMLH1、hMSH2及PCNA在肺癌组织中的表达及意义

 目的　探讨人类错配修复基因hMLH1、hMSH2及增殖细胞核抗原PCNA在肺癌组织中的表达及意义。方法　运用免疫组织化学S P法对 5 6例肺癌组织中hMLH1、hMSH2及PCNA的表达进行检测。结果　 5 6例肺癌组织中hMLH1的阳性表达率为 35 % ,hMSH2阳性表达率为 2 8.6 % ,分化程度高者阳性率显著高于分化程度低者 (P <0 .0 1) ,有淋巴结转移者hMLH1及hMSH2阳性率低于无淋巴结转移者 (P <0 .0 5 ) ,不同病理组织学类型之间hMLH1及hMSH2表达无显著差别 (P >0 .0 5 ) ;5 6例肺癌组织中分化程度低者PCNA标记指数高于分化程度高者 (P <0 .0 1) ,有淋巴结转移者PCNA标记指数高于无淋巴结转移者 (P <0 .0 5 ) ,hMLH1及hMSH2阴性表达者的PCNA标记指数明显高于hMLH1及hMSH2阳性表达者 (P <0 .0 1) ,不同病理组织学类型之间PCNA标记指数无显著差别 (P >0 .0 5 )。结论　hMLH1及hMSH2基因的缺陷及PCNA的表达与肺癌的发生发展过程并与分化程度及有否淋巴结转移有关     

原发性MALT淋巴瘤API2-MALT1融合基因多种变异体的表达及其意义

目的:检查API2-MALT1融合基因多种变异体mRNA在MALT淋巴瘤中的表达情况,探讨其表达与MALT淋巴瘤的临床病理特征及预后的关系.方法:收集胃和肺MALT淋巴瘤石蜡包埋标本共29例,慢性淋巴结炎5例.采用RT-PCR和巢式PCR相结合检测MALT淋巴瘤中API2-MALT1的mRNA.将29例分为API2-MALT1mRNA表达组及未表达组,了解两组患者临床病理学特征和预后的差异.结果:MALT淋巴瘤中两种API2-MALT1变异体被检出,总检出率为48.2%,慢性淋巴结炎未检出,与未表达组相比,表达组临床病理分期偏低,细胞增殖活性和淋巴结受累有降低和减轻的趋势,两组间病变范围、浸润深度等特征及预后无明显差异.结论:API2-MALT1mRNA的表达可能与MALT淋巴瘤的淋巴结受累、临床病理分期及细胞增殖有关,与MALT淋巴瘤的浸润深度、病变范围及预后等无明显相关:不同的变异体表达与MALT淋巴瘤的发生部位有关.     

E2F-1和Rb基因在食管鳞状细胞癌中的 表达及临床意义

 目的 研究E2F-1和Rb基因在食管鳞状细胞癌中的表达情况,探讨其在食管鳞状细胞癌发生发展中的规律与临床病理关系。方法 应用免疫组化方法检测60例食管鳞状细胞癌和50例正常食管组织中E2F-1和Rb基因的表达情况。结果 食管鳞状细胞癌中E2F-1的阳性表达率为73.3％,显著高于癌旁正常组织黏膜中的36.0％（P<0.01）,E2F-1的表达与食管鳞状细胞癌的分期、分化及淋巴结转移有相关性（P<0.05）。Rb在食管鳞状细胞癌中的阴性表达率为30.0％,显著高于癌旁正常组织中的12.0％（P<0.05）,Rb在食管鳞状细胞癌中的表达与分化及淋巴结转移有关（P<0.05）,但尚不能认为与分期有关。结论 E2F-1和Rb在食管鳞状细胞癌中的表达呈负相关,即E2F-1过度表达而Rb表达有一定程度缺失,在正常食管组织中的表达亦有差异。     

凋亡调控基因Mcl-1和bcl-2在反应性及肿瘤性淋巴组织中的表达及其意义

目的 :观察Mcl 1和bcl 2在反应性和肿瘤性淋巴组织中的表达 ,探讨其在肿瘤发生和发展过程中的作用。方法 :收集临床资料完整的反应性淋巴组织增生石蜡包埋标本 36例 ,非霍奇金淋巴瘤(NHL) 78例和霍奇金病 (HD) 10例 ,采用免疫组化方法染色观察Mcl 1和bcl 2表达。结果 :反应性淋巴组织中Mcl 1阳性细胞主要分布在生发中心和滤泡间区 ,而bcl 2阳性的套区淋巴细胞为Mcl 1阴性。 78例NHL中 ,有 5 7例不同程度地表达Mcl 1蛋白 ,5 3例表达bcl 2 ,B细胞肿瘤中两者阳性率高于T细胞肿瘤。 10例HD中有 9例Mcl 1 bcl 2阳性。结论 :Mcl 1作为一种凋亡抑制基因在淋巴组织的表达不同于bcl 2 ;鉴于两者在淋巴组织肿瘤中的广泛分布 ,提示其在淋巴瘤细胞凋亡调控中可能起着重要作用     

EB病毒潜伏膜蛋白LMP1、VEGF和cyclinD1在乳腺癌中的表达及其相关性

目的:探讨乳腺癌中EB病毒(Epstein-Barr virus,EBV)潜伏膜蛋白1(latent membrane protein 1,LMPl)、血管内皮生长因子(vascular endothelial growth factor,VEGF)和细胞周期蛋白D1(cyclinD1)的表达及其相关性.方法:收集乳腺癌标本构建组织芯片,应用免疫组化方法检测LMP1、VEGF和cyclinD1的表达,并结合临床病理因素进行相关分析.结果:乳腺癌组织中LMP1、VEGF及cyclinD1的表达率分别为17.8％(19/107)、85.0％ (91/107)和64.5％ (69/107);LMP1和cyclinD1的表达与患者年龄、肿瘤大小、病理学类型、淋巴结转移及脉管侵犯均无明显相关性(P＞0.05),而两者的表达均与组织学分级有关(P＜0.05);VEGF的表达与患者年龄、肿瘤大小、病理学类型、组织学类型及脉管侵犯均无明显相关(P＞0.05),而与淋巴结转移存在相关性(P＜0.05);LMP1的表达与VEGF和cyclinD1均明显相关(P＜0.05),同时,VEGF与cyclinD1表达明显相关(P＜0.05).结论:乳腺癌中LMP1可能直接上调VEGF的表达,或者LMP1通过促进cyclinD1的表达来上调VEGF的表达,从而对乳腺癌的淋巴转移及发生发展起到促进作用.     

EBER1/2、LMP-1在NK/T细胞淋巴瘤中的表达

目的　探讨NK /T细胞淋巴瘤与EB病毒 (EBV )的关系。方法　收集 2 6例NK /T细胞淋巴瘤 (淋巴结内 10例 ,淋巴结外 16例 ) ,采用免疫组织化学S P法确定瘤细胞本质 ,用原位杂交法检测EBV编码的RNA (EBER 1/2 )。结果　①在 2 6例NK /T细胞淋巴瘤中 ,EBER1/2检出率为 46 .2 % (12 /2 6 ) ,其中淋巴结内检出率为 10 .0 % (1/10 ) ,淋巴结外检出率为 6 8.8% (11/16 ) ,2组比较有非常显著性差异 (P <0 .0 1)。②在淋巴结外NK/T细胞淋巴瘤中 ,EBER 1/2在鼻腔检出率为 90 .0 % (9/10 ) ,其它部位为 33 .3 % (2 /6 ) ,2组比较有显著性差异 (P <0 .0 5 )。③EB病毒潜伏膜蛋白 (LMP 1)在EBER1/2阳性病例中的检出率为16 .7% (2 /12 )。结论　EBV在NK /T细胞淋巴瘤的发生中有一定作用 ,并具有部位依赖性的特点 ;EBV在NK /T细胞淋巴瘤中的潜伏感染模式不完全一致。     

Analysis of c-myc, bcl-1 and bcl-2 Translocations in Human Lymphoma by Pulsed-Field Gel Electrophoresis

Translocations of the c-myc, bcl-2 and the putative bcl-1 oncogene are recurrent events in B-cell lymphoma. Since it is likely that the rearranged genes contribute to the malignant phenotype of the tumor cells, such oncogene translocation is of major interest. The molecular detection of translocations using conventional Southern hybridization analysis is complicated by the fact that translocation breakpoints are dispersed over large chromosomal regions. In order to overcome this problem we used pulsed-field gel electrophoresis (PFGE) to detect c-myc, bcl-2 and bcl-1 translocations in 29 lymph node biopsies.

C-myc translocation could not be detected in this group, either with standard Southern analysis or PFGE. Translocations of the bcl-2 gene were detected by PFGE in 5 samples and the breakpoints were mapped in all cases to the third exon of bcl-2 by standard Southern analysis. Furthermore, we also found rearrangements of the bcl-1 locus in 3 samples. Mapping of the breakpoint failed in one of these cases, which strongly indicates the existence of a breakpoint outside the bcl-1 major breakpoint region. Thus, PFGE allows the rapid detection of translocations in human lymphomas within large stretches of DNA.     

尾型同源盒转录因子-2(CDX2)在人大肠肿瘤中的表达

 目的 研究CDX2在人大肠腺癌发生发展过程中的作用及其与大肠腺癌淋巴结转移、TNM分期的关系。方法 采用免疫组化SP法观察CDX2蛋白的表达特点。结果 CDX2蛋白定位于细胞核,从大肠腺瘤→无淋巴结转移的大肠腺癌→有淋巴结转移的大肠腺癌、从高分化→中分化→低分化大肠腺癌以及从TNM分期的Ⅰ期→Ⅱ期→Ⅲ期→Ⅳ期之间其蛋白表达逐渐降低。结论 CDX2的下调在大肠腺癌的发生发展过程中起着一定的作用,并可作为判断大肠腺癌患者预后的一个良好指标。     

Complement Receptor 1 (CR1) Expression in Chronic Myeloid Leukemia

The complement receptor 1 (CR1), also called CD35, is a polymorphic glycoprotein which mediates a variety of neutrophil functions, including phagocytosis and, probably, tumor cell cytotoxicity. The role played by this molecule in chronic myeloid leukemia (CML) is not yet well understood. CML frequently shows a marked decrease of CR1 antigens on both the neutrophil population and myeloid precursors. This reduced expression appears to be related to disease activity, since patients at more advanced clinical stages, as well as those who develop blastic crisis, have been found to express the lowest levels of CR1 antigens. At the onset of the disease low CR1 expression on CML neutrophils seems to be associated with a higher risk of blastic transformation. Furthermore, CML neutrophils deficient in CR1 lack the ability to respond to PMA stimulation, suggesting a failure in CR1 granular storage. In patients lacking CR1, the number of receptors increased to normal levels following exposure of CML cells to therapeutic concentrations of recombinant alpha interferon.

The role played by the CR1 molecule in sustaining neutrophil-mediated tumor cell cytotoxicity has yet to be definitively proved; studies performed by our group are relevant here, since complete suppression of tumor lysis following receptor neutralization by anti CR1 monoclonal antibodies was demonstrated in a large number of normal and CML individuals. In CML patients, the evidence of a direct relationship between lytic activity and antigen receptor levels seems to further support the involvement of CR1 molecules in tumor cell lysis function. Whether CR1 has a causative role in CML has still to be demonstrated, since various biological studies seem to support the theory that CR1 deficiency may represent a secondary event. Further studies are needed in order to clarify this intriguing point, and to evaluate CR1 expression during normal and leukemic myeloid differentiation pathways.     

膜联蛋白A1和A2在胆囊良恶性病变组织中的表达水平及其与胆囊腺癌临床病理特征的关系

目的 研究膜联蛋白A1(ANXA1)和膜联蛋白A2(ANXA2)在胆囊腺癌、癌旁组织、胆囊腺瘤性息肉和慢性胆囊炎组织中的表达水平及其与胆囊腺癌临床病理特征之间的关系.方法 选取108例胆囊腺癌、46例癌旁组织、15例胆囊腺瘤性息肉和35例慢性胆囊炎手术切除标本,常规制作石蜡包埋切片.采用免疫组织化学EnVsionTM法检测各组织中ANXA1和ANXA2的表达水平.结果 ANXA1和ANXA2在胆囊腺癌组织中的阳性表达率分别为59.3%和56.5%,其评分值分别为3.2±0.9和3.4±0.8;在癌旁组织中的阳性表达率分别为34.8%和30.4%,其评分值分别为1.1±0.8和1.0±0.8;在胆囊腺瘤性息肉组织中的阳性表达率分别为26.7%和26.7%,其评分值分别为0.9±0.7和0.9±0.8;在慢性胆囊炎组织中的阳性表达率分别为17.1%和20.0%,其评分值分别为0.7±0.9和0.8±0.8.胆囊腺癌组织中ANXA1和ANXA2的阳性表达率及其评分均高于癌旁组织、胆囊腺瘤性息肉组织和慢性胆囊炎组织(均P＜0.05).ANXA1和(或)ANXA2阳性表达的癌旁组织、胆囊腺瘤性息肉和慢性胆囊炎上皮均呈轻至重度不典型增生.高分化腺癌、肿瘤最大径＜2 cm、淋巴结未转移及未侵犯周围组织的胆囊腺癌患者ANXA1和ANXA2的阳性表达率,均明显低于中或低分化腺癌、肿瘤最大径≥2 cm、有淋巴结转移及侵犯周围组织者(均P＜0.05).在胆囊腺癌组织中,ANXA1和ANXA2的表达呈高度一致性(x2=67.84,P＜0.01),其评分值之间呈高度密切正相关(r=0.78,P＜0.01).Kaplan-Meier单因素分析及Cox多因素回归分析结果均显示,ANXA1和ANXA2的表达均不是影响胆囊腺癌预后的重要因素.结论 ANXA1和ANXA2的表达水平可能是反映胆囊腺癌发生、发展及生物学行为的重要生物学指标,但并不能预测胆囊腺癌患者的预后.     

t(2;5) (p23;q35)-A Specific Chromosome Abnormality in Large Cell Anaplastic (Ki-1) Lymphoma

Chromosome abnormalities of three patients with Ki-1 lymphoma are presented. In order to be included in the study each case fulfilled the following criteria: the majority of the tumour cells were positive for the Ki-1 antigen (CD30), and the cells were large with relatively abundant, slightly basophilic cytoplasm. In all cases, a major proportion of mitoses contained a complicated clonal chromosome abnormality. Two patients had a 2;5 translocation; and the third had break points at 14q32 and 2p12. The latter patient showed expression of B-cell antigens and had rearrangements in the immunoglobulin heavy chain and kappa light chain genes. The two patients with the 2;5 translocation were epithelial membrane antigen positive, but did not exhibit rearrangements of immunoglobulin/T-cell receptor genes or expression of T-/B-cell antigens.     

c-erbB-2 and c-erbA-1 (ear-1) Gene Amplification and c-erbB-2 Protein Expression in Japanese Breast Cancers: Their Relationship to the Histology and Other Disease Parameters

We studied c- erb B-2 and c- erb A-1 ( ear -1) gene amplification, and c- erb B-2 protein expression in 123 primary Japanese breast cancers. c- erb B-2 amplification was found in 19 of the 123 tumors (15%), and c- erb A-1 was coamplified in 7 of the 19. The presence or absence of c- erb B-2 amplification correlated with the grade of cellular atypism ( P = 0.008), or that of mitotic index ( P = 0.002), but not with the histologic types. The tumor size ( P = 0.04) and the lymph node status ( P = 0.06) were associated, but the patients' age, the TNM stage, or the presence or absence of estrogen or progesterone receptors was not associated, with c- erb B-2 amplification. There were no differences in the histologic type, cellular atypism, mitotic index, and other disease parameters between tumors with c- erb B-2 amplification only and those with coamplification of c- erb B-2 and c- erb A-1. Paraffin sections from all 19 tumors with c- erb B-2 amplification, and those from only one of 104 tumors without the amplification were positively stained with polyclonal anti-c- erb B-2 protein antibody. Since the correlation between the amplification and the protein expression was excellent, such immunohistochemical studies may be substituted for the time-consuming DNA studies using Southern blotting.     

贲门癌中c-erbB-2、MTA1及E-cadherin的表达

 目的探讨c-erbB-2、MTA1及E-cadherin蛋白在贲门癌组织中的表达与肿瘤生物学行为的相关性,以及它们三者之间的相关性。方法采用免疫组织化学方法对60例贲门癌组织和18例癌旁组织中c-erbB-2、MTA1及E-cadherin蛋白的表达情况进行检测。结果c-erbB-2的表达与贲门癌的浸润、转移呈正相关,与分化程度呈负相关(P<0.05)。MTA1的表达与贲门癌的浸润深度无显著相关性,与贲门癌的淋巴结转移呈正相关,与分化程度呈负相关(P<0.05)。E-cadherin的表达与贲门癌的浸润深度、转移呈负相关(P<0.05),与分化程度无关。Spearman等级相关分析显示,c-erbB-2与MTA1的表达呈显著正相关(rs=0.276,P<0.05),MTA1与E-cadherin的表达呈负相关(rs=-0.293,P<0.05)。结论c-erbB-2与MTA1的高表达及E-cadherin的表达减少可能是促进贲门癌浸润和转移的重要因素。     

MYC/BCL2双表达大B细胞淋巴瘤中PD-L1的表达及其临床意义CSCD

目的探讨MYC/BCL2双表达大B细胞淋巴瘤(DEL)与程序性细胞死亡受体-配体1(PD-L1)mRNA、蛋白表达的相关性及其临床意义。方法收集90例弥漫大B细胞淋巴瘤(DLBCL)病例,采用免疫组织化学染色检测MYC、BCL2蛋白并分组,双标记染色法检测各组病例的肿瘤细胞或微环境细胞中PD-L1表达;实时荧光PCR技术(Real-time PCR,qPCR)检测DEL组与non-DEL组PD-L1 mRNA相对表达量;收集临床病理资料并随访,对实验数据进行统计学分析。结果90例样本中28例为DEL,肿瘤细胞和微环境中PD-L1+分别为22例和26例。DEL组肿瘤细胞和微环境中PD-L1+分别为14例和9例;肿瘤细胞和微环境细胞PD-L1蛋白表达与DEL存在相关性(P<0.05);PD-L1 mRNA相对表达量在DEL与non-DEL组间存在显著差异(P=0.012);DEL组中PD-L1+与IPI评分和B症状的出现有关(P=0.007、0.021);Kaplan-Meier显示DEL中PD-L1+、肿瘤微环境PD-L1阳性(mPD-L1+)与患者预后相关(P=0.005、0.001)。结论DEL患者PD-L1 mRNA及蛋白表达都明显上调且与患者不良预后相关,PD-L1可作为DEL患者不良预后评估的危险因素。     

Expression of the Circadian Clock Genes Per1 and Per2 in Sporadic and Familial Breast Tumors

There is a growing body of evidence implicating aberrant circadian clock expression in the development of cancer. Based on our initial experiments identifying a putative interaction between BRCA1 and the clock proteins Per1 and Per2, as well as the reported involvement of the circadian clock in the development of cancer, we have performed an expression analysis of the circadian clock genes Per1 and Per2 in both sporadic and familial primary breast tumors and normal breast tissues using real-time polymerase chain reaction. Significantly decreased levels of Per1 were observed between sporadic tumors and normal samples (P < .00001), as well as a further significant decrease between familial and sporadic breast tumors for both Per1 (P < .00001) and Per2 (P < .00001). Decreased Per1 was also associated with estrogen receptor negativity (53% vs 15%, P = .04). These results suggest a role for both Per1 and Per2 in normal breast function and show for the first time that deregulation of the circadian clock may be an important factor in the development of familial breast cancer. Aberrant expression of circadian clock genes could have important consequences on the transactivation of downstream targets that control the cell cycle and on the ability of cells to undergo apoptosis, potentially promoting carcinogenesis.