p16 protein expression is associated with a poor prognosis in squamous cell carcinoma of the lung

An immunohistochemical analysis for p16 protein was performed in 171 patients with non-small-cell lung cancer (NSCLC). Sixty-two carcinomas (36.3%) were classified as p16-negative. p16-negative tumours in squamous cell carcinomas (SCCs) were significantly more than those in adenocarcinomas (P = 0.039). There was no significant difference in survival according to tumour p16 status in patients with NSCLCs or in patients with adenocarcinomas. In contrast, of patients with SCCs, the 5-year survival rate of patients with p16-negative tumours was significantly lower than those with p16-positive tumours (P = 0.001). Especially, the survival of patients with p16-negative tumours was significantly worse than that of patients with p16-positive tumours in the early stage of the SCC, e.g. stage I (P = 0.005). Multivariate analysis showed that p16 status and nodal status were significant prognostic factors for the survival of patients with SCCs of the lung (P = 0.024 and P = 0.008 respectively). In conclusion, our study showed that alteration of p16 was one of the significant factors of a poor prognosis in SCCs of the lung, and that p16 might play an important role in some SCCs of the lung due to its high prevalence and prognostic value.     

Loss of p16 expression is associated with the stem cell characteristics of surface markers and therapeutic resistance in estrogen receptor-negative breast cancer

Triple-negative breast cancer [TNBC, which is negative for the estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2] is a high-risk form of the disease without a specific therapy. DNA microarray and immunohistochemical analyses have shown that most TNBCs fall within the basal-like histological subset of breast cancers, which frequently exhibit inactivation of the retinoblastoma tumor suppressor (Rb) and upregulation of the cyclin-dependent kinase inhibitor p16(INK4a) (p16). However, downregulation of p16 expression has been observed in some basal-like breast cancer cell lines, suggesting that such cells can be divided into two groups according to Rb and p16 status. We now show that cells that are CD44(+) and CD24(-) , a phenotype associated with stem-like breast cancer cells, are more abundant in ER(-) /p16(-) breast cancer cell lines than in ER(-) /p16(+) lines. It was also found that p16 expression was downregulated in mammospheres from an ER-negative breast cancer cell line. Depletion of p16 by RNA interference in ER-negative breast cancer cells increased the percentage of CD44(+) /CD24(-) cells and increased the expression of mRNA of the ES-like genes Nanog, Oct4, and Sox2 through an Rb-independent pathway. Furthermore, such depletion of p16 reduced chemosensitivity. The loss of p16 expression may thus reduce the response of ER-negative breast cancer cells to chemotherapy by conferring cancer stem cell-like properties. Consistent with this conclusion, immunohistochemical analysis of the clinical samples suggests that low p16 expression in TNBC is associated with resistance to preoperative chemotherapy.     

p16INK4a protein expression is associated with poor survival of the breast cancer patients after CMF chemotherapy

Immunohistochemical assay for p16 protein expession was performed in 192 breast carcinoma patients treated with adjuvant chemotherapy. p16 expression was observed in 78 cases (40.6%). The frequency of p16 expression significantly decreased in moderately differentiated (histologic grade II) cancers, 20 (19.6%) of 102. In poorly differentiated cancers (histologic grade III), p16 expression was not observed in all 16 cases. p16 expression was significantly associated with histologic grade of the breast carcinomas (p<0.001). The proliferative index (PI: S + G2/M) of individual tumors was measured by DNA flow cytometry. In 114 tumors with PI less than 20%, p16 expression was observed in 59 tumors (49.1%). In the tumors with PI equal or more than 20%, p16 expression was observed in 22 (28.2%) of 78 cases. p16 expression was significantly decreased in the tumor with higher PI (p=0.003). For the other clinicopathologic variables, no significant association was found with p16 expression status. Immunohistochemical assay for p53 protein expression was performed on the same breast carcinomas. There was no significant association between p16 and p53 expression in breast carcinomas. During median follow-up period of 52 months (range: 40–72 months), 46 patients (25.8%) had recurrent disease and 32 patients (18.91%) died of recurrent disease. p16 expression was observed in 20 (43.5%) of 46 patients with recurrent disease, while its expression was observed in 58 patients (39.7%) of 146 patients who were free of recurrence during the study period. p16 expression had no significant impact on predicting recurrence of breast carcinoma. Fourteen patients (12.2%) of 114 patients whose tumors did not show p16 expression died of recurrent breast carcinoma, whereas 18 patients (23.1%) of 78 patients with p16 expressing tumor died during the follow-up period. There was a significant difference of patient survival according to p16 expression status (p=0.039). These results indicate that p16 expression is useful in predicting response to chemotherapy in breast cancer patients. p16 protein seems to have a role in tumor growth and differentiation of the breast carcinoma.     

p16和p27蛋白在乳腺癌的表达及其意义

目的 :探讨p16和p2 7在乳腺癌的表达特点及其判断乳腺癌患者预后的意义。方法 :应用免疫组化ABC法检测 89例乳腺癌的p16、p2 7的表达情况。结果 :89例乳腺癌中 ,p16蛋白阳性表达率4 8 3% (4 3/ 89) ,p2 7蛋白阳性表达率 57.3% (51/ 89)。p16蛋白在腋淋巴结转移阳性组表达率 31.8%(14/ 4 4 ) ,显著低于腋淋巴结转移阴性组表达率 6 4 .4 % (2 9/ 4 5) (P <0 .0 1)。p2 7蛋白在浸润性乳腺癌组和腋淋巴结转移阳性组表达率分别为 52 .0 % (39/ 75)、38.6 (17/ 4 4 ) ,显著低于非浸润性乳癌腺组和腋淋巴结转移阴性组的表达率 85.7% (12 / 14)、75.6 % (34/ 4 5) (P <0 .0 5、P <0 .0 1)。结论 :p16蛋白与p2 7蛋白的缺失表达均与乳腺癌的生物学行为有关。p2 7蛋白检测在判断乳腺癌患者预后方面比p16蛋白检测可能有更重要意义。     

p16和Rb基因产物在非小细胞肺癌的表达

目的　研究非小细胞肺癌 (NSCLC)中p16、Rb蛋白表达及二者的关系。方法　应用免疫组织化学技术 (SP法 )检测 74例NSCLC和 10例正常肺组织中p16、Rb蛋白的表达情况。结果　p16蛋白在NSCLC的缺失率为 45 .95 % ,显著高于正常肺组织 (P <0 .0 1) ,并与淋巴结转移有密切关系 (P <0 .0 1)。Rb蛋白在NSCLC的缺失率为 2 8.3 8% ,与正常肺组织差异无显著性 (P >0 .0 5 )。p16蛋白与Rb蛋白表达呈负相关 (P <0 .0 5 )。结论　p16缺失与可能NSCLC的发生、转移有密切关系。p16与Rb可能通过负反馈机制相互调节。     

乳腺增生病p16蛋白表达及p16基因突变

目的　探讨p16基因在乳腺癌发生早期的作用。方法　用免疫组化方法检测 36例乳腺单纯性增生、31例不典型增生、14例导管内癌和 16例浸润性导管癌中p16蛋白的表达 ,用PCR SSCP和DNA测序技术检测上述组织中p16基因突变。结果　p16蛋白在单纯性增生、不典型增生、导管内癌、浸润癌中的表达缺失率分别为 0、16 .1%( 5 /31)、35 .7%( 5 /14 )、43.7%( 7/16 ) ,在 1例不典型增生、1例导管内癌、1例浸润性导管癌中检测p16基因突变。结论　p16蛋白表达缺失出现在乳腺癌发生的早期阶段 ,这种表达异常似乎与p16基因突变无明显关系。     

DEK is highly expressed in breast cancer and is associated with malignant phenotype and progression

DEK proto-oncogene (DEK) has been demonstrated as an oncogene and is associated with the development of many types of tumor; however, the expression and role of DEK in breast cancer remain unknown. The present study aimed to determine the role of DEK in the progression of breast cancer. The expression of DEK in 110 breast cancer tissues and 50 adjacent normal breast tissues was examined using immunohistochemistry. Furthermore, DEK expression was upregulated by DEK transfection or downregulated by DEK shRNA interference in MCF7 cells. Proliferative and invasive abilities were examined in MCF7 cells using MTT assay, colony-formation assay and transwell invasion assays. The results demonstrated that DEK expression level was significantly increased in breast cancer tissues compared with normal breast tissues. Furthermore, high DEK expression was associated with high histological grade, lymph node metastasis, advanced Tumor-Node-Metastasis stage and high Ki-67 index; however, DEK expression was not associated with the expression level of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. High DEK expression indicated poor prognosis in patients with breast cancer. DEK overexpression upregulated the protein expression of β-catenin and Wnt and increased the proliferative and invasive abilities of breast cancer cells. DEK downregulation had the opposite effect. Taken together, the results from the present study demonstrated that high expression of DEK was common in patients with breast cancer and was associated with progression of the disease and poor prognosis, and that DEK overexpression promoted the proliferative and invasive abilities of breast cancer cells.     

乳腺癌中HPV与p53、Rb蛋白表达的关系及对预后的影响

目的:研究乳腺癌中HPV与p53、Rb蛋白表达的关系及对预后的影响。方法:免疫组化法检测96例乳腺癌组织中p53、Rb蛋白的表达,采用流式荧光杂交技术检测标本中HPV的感染情况并分型。SPSS 17.0软件对试验结果进行统计分析。结果:96例乳腺癌标本中,p53、Rb、HPV的阳性率分别为59.38%、87.50%、7.29%,p53阳性表达率与淋巴结转移率呈正相关（P<0.05）,p53、Rb表达与HPV感染均无明显相关性（P=0.26,P=0.59）。p53、Rb及HPV的表达与预后无相关性（P=0.628,P=0.084,P=0.699）。结论:HPV与p53、Rb的表达在乳腺癌中无明显相关性,p53高表达的患者淋巴结转移率较高。     

p170和p53在乳腺癌组织的表达及临床意义

目的：探讨乳腺癌组织中p170和053的表达及两者之间的关系和临床意义。方法：采用S—P免疫组化法检测96例乳腺癌石蜡标本中p170和053蛋白的表达，分析其与临床病理因素的关系及两者的相关性。结果：96例乳腺癌组织中p170阳性表达率为65．25％（54／96），其表达与患者年龄、肿瘤大小、病理分级、ER和PR表达及淋巴结转移无关。053阳性表达率为41．67％（40／96），其表达与病理分级呈正相关、与患者年龄、病理分型、ER和PR表达及淋巴结转移无明显相关，p170与p53的表达成正相关。结论：p170与p53的表达呈正相关，他们是重要的病理指标，对肿瘤化疗药物的选择有指导意义。     

p16和Rb在胆道良及其意义恶性病变中的表达及其意义

目的研究p16、Rb在胆道良恶性病变中的表达和临床意义.方法应用免疫组化S-P法测定41例肝外胆管癌中p16、Rb的表达,以13例慢性胆管炎作为对照.结果肝外胆管癌组p16阳性率为51.2%(21/41).其中,高中分化癌组、低分化癌组、转移组、无转移组阳性率分别为53.6%(15/28)、46.2%(6/13)、31.3%(5/16)和64.0%(16/25);胆管炎组阳性率为92.3%(12/13).肝外胆管癌组与胆管炎组间、无转移组与转移组间差异有显著性(P<0.01,P<0.05),高中分化癌组与低分化癌组间差异无显著性(P>0.05).肝外胆管癌组Rb阳性率为58.5%(24/41).其中,高中分化癌组、低分化癌组、转移组、无转移组Rb阳性率分别为71.4%(20/28)、30.8%(4/13)、37.5%(6/16)和72.0%(18/25);胆管炎组阳性率为92.3%(12/13).肝外胆管癌组与胆管炎组间、高中分化癌组与低分化癌组间、无转移组与转移组间差异有显著性(P<0.05).24例Rb阳性病例中,p16阳性率为37.5%(9/24);17例Rb阴性病例中,p16阳性率为70.6%(12/17),两者表达呈负相关(P<0.05),Kendall相关系数τb=-0.33.结论肝外胆管癌组织中存在p16、Rb异常表达,均与转移有关,Rb异常表达还与肝外胆管癌病理分级有关.上述两指标可作为判断患者预后的参考指标.     

乳腺癌组织中Cyclin D1及p16蛋白表达的联合检测及其意义

目的:探讨乳腺癌中Cyclin D1及p16蛋白表达的相关性及其临床意义。方法:LSAB法检测多种乳腺组织中Cyclin D1及p16蛋白的表达情况,结合有关临床资料,分析Cyclin D1和p16蛋白表达异常与乳腺癌中重要的临床病理因素的关系。结果:62例乳腺癌组织中,Cyclin D1蛋白过度表达占48·4%,其表达与乳腺癌组织学分级呈明显正相关,且Cyclin D1蛋白过度表达更常见于ER、PR阳性的乳腺癌中。乳腺癌旁组织中Cyclin D1蛋白过度表达为20·0%,其他几种乳腺组织很少有CyclinD1蛋白的过度表达。p16蛋白仅在58·1%的乳腺癌组织中有表达,且p16的表达与组织学分级程度有负相关关系。正常乳腺组织中未见p16蛋白的异常。结论:乳腺癌组织中存在着Cyclin D1蛋白的过度表达及p16蛋白的异常,二者对乳腺癌组织的增殖分化有一定的影响。     

Expression of the transcription factor CTCF in invasive breast cancer: a candidate gene located at 16q22.1

CTCF is a ubiquitous 11-zinc-finger protein that plays a role in gene silencing or activation, chromatin insulation and genomic imprinting. The CTCF gene has been mapped to the chromosome band 16q22.1 that shows frequent loss of heterozygosity in breast cancer. The E-cadherin gene is the known tumour suppressor gene (TSG) at this region in lobular carcinomas; however, the target gene in the more frequent ductal tumours is still unknown. Since CTCF targets include TSGs and oncogenes and it has the ability to inhibit cell growth and proliferation, it has been suggested that it may be the target gene at the 16q22.1 in ductal carcinomas. In the present study, tissue microarray technology was used to study the expression pattern of CTCF immunohistochemically in 344 cases of invasive breast carcinoma and its expression was correlated with clinicopathological variables and patient outcome. Results showed that breast tissues express CTCF in the parenchymal cells of the normal ducts and lobules but with a variable percentage of positive cells. Staining of CTCF was detected in the nuclei and cytoplasm of the malignant cells, but no significant loss or decrease of expression was noticed in association with any specific tumour type. There was a significant correlation between expression of CTCF and histological grades; lower expression was associated with grade 3 tumours. Cytoplasmic expression was associated with increased tumour size and with the presence of vascular invasion. However, no association was found between CTCF expression and tumour type, lymph node stage, oestrogen receptor expression or patient outcome. In conclusion, the current results show that CTCF, although it may play a role in breast carcinogenesis, is unlikely to be the TSG targeted by the 16q22.1 loss in breast cancer and thus another gene or genes at this region remain to be identified.     

p16(INK4a) promoter methylation and protein expression in breast fibroadenoma and carcinoma

The potential role of p16(INK4a) methylation in breast cancer is controversial whereas there are no data on fibroadenoma. To assess if inactivation of p16(INK4a) by promoter hypermethylation occurs in this hyperproliferative benign breast lesion or, on the contrary, it is strictly related to the carcinogenic process, we have tested the different histological components of 15 cases of fibroadenoma and the intraductal and infiltrating components of 15 cases of carcinoma and their adjacent non-tumoral epithelium. All samples were obtained by laser-assisted microdissection. The relationship between promoter methylation status, immunohistochemical protein expression and ki67 proliferative activity was evaluated for each lesion. Our data demonstrate that hypermethylation of p16(INK4a) promoter is a common event occurring at similar frequency in all the different histological areas of the benign and malignant breast lesions taken into exam. Conversely, protein p16 expression, although heterogeneously distributed within the section, is considerably higher in breast carcinoma as compared to fibroadenoma in both tumoral and non-tumoral epithelia and stroma. The protein localization was almost exclusively nuclear in fibroadenoma and non-tumoral epithelia whereas, in carcinoma, the staining was both nuclear and cytoplasmic or cytoplasmic alone. Furthermore, in a subset of fibroadenoma with higher proliferative activity, p16 protein expression was substantially decreased as compared to those showing lower proliferation. We did not observe this association in carcinomas. Our data demonstrate that the hypermethylation of the p16(INK4a) promoter is not specifically associated with malignancy and that, on the contrary, the overexpression of p16 and its cytoplasmic sequestration is a feature of breast carcinoma.     

p16基因mRNA及其编码蛋白在人乳腺癌中的表达

目的：研究人乳腺癌中ｐ１６基因ｍＲＮＡ及其编码蛋白的表达水平与肿瘤发生中预后的相关性。方法：采用免疫组化和原位杂交方法分别对１１例乳腺良性肿瘤和５９例乳腺癌中的ｐ１６基因及其编码蛋白进行检测。结果：ｐ１６基因蛋白表达水平与乳腺肿瘤的良、恶性显著相关（Ｐ〈０．０５）;ｐ１６基因ｍＲＮＡ及其蛋白表达水平与乳腺癌的腋窝淋巴结转移呈现显著负相关（Ｐ〈０．０５）,而与乳腺癌的术后自下而上期呈显著正相关（Ｐ〈     

新疆不同民族食管癌中p53、p16、Rb蛋白的表达及其意义

目的　探讨 p5 3、p16、Rb蛋白在新疆不同民族食管癌中的表达及意义。 方法　应用免疫组化技术检测 119例不同民族食管癌组织中 p5 3、p16、Rb蛋白的表达。 结果　新疆食管癌 p5 3、p16、Rb蛋白检出率在不同民族间的阳性表达率均无显著性差异 (P >0 .0 5 )。三者阳性表达率与组织学分级无关 (P >0 .0 5 ) ;p5 3、p16阳性均与肿瘤浸润深度以及淋巴结转移有关 (P <0 .0 5 ) ,而Rb阳性仅与淋巴结转移有关 (P <0 .0 5 )。Rb与p16的表达密切相关 (P <0 .0 1)。结论　 1.食管癌组织内三者蛋白表达在新疆不同民族之间无显著性差异。 2 .检测三者蛋白的表达有助于判断食管癌的恶性程度以及推断临床预后。     

原发性和继发性胶质母细胞瘤中p53 、p16 和Rb 的表达及意义

 目的 探讨p53、p16和Rb基因在原发性和继发性GBM中的表达差异性及意义。方法 应用RT—PCR和Western-blot检测14例原发性和16例继发性GBM中p53，p16mRNA和蛋白表达，免疫组织化学法检测Rb表达。结果 Rb免疫组织化学染色显示正常脑组织中无表达，14例原发GBM中有3例表达缺失（21．4％），16例继发GBM中有2例表达缺失（11．1％）。RT-PCR和Westernblot对比原发和继发GBM中p53和p16的表达，发现所有继发GBM中p53表达强度较原发GBM明显增加，14例原发GBM中有5例缺失（36．（1％），继发GBM中仅有1例表达缺失（6．25％）。p16表达缺失明显减少。结论 Rb的表达缺失在原发和继发GBM中没有明显的差异。细胞周期调节基因p53在mRNA和蛋白水平表达增加和p16在同样水平表达缺失是原发与继发GBM重要的细胞周期调控基因上的变化，可能是基因治疗GBM的重要靶点之一。     

p16基因表达与胃癌临床生物学特及预后的研究

目的：检测与分析p16基因表达产物在胃癌组织中的表达。探讨其与胃癌术后复发、转移及生存率的关系。方法：应用免疫组织化学方法检测84例胃癌标本中P16蛋白的表达。结果：84例中p16表达阳性率44．05％,转移淋巴结表达阳性率37．50％,明显低于正常组织及胃良性息肉。p16表达与组织学无关,与肿瘤浸润深度、临床分期及淋巴结转移有关。随访中发现,阴性表达者死亡率高、中位生存期短,转移复发率均高于阳性表达者（P＜0．01）。结论：p16蛋白异常表达在胃癌的发生发展过程中起重要作用。其可能成为临床评估肿瘤生物学行为及判断预后的标志之一。     

p16蛋白在宫颈癌中的表达及其与患者临床特征和预后的关系

目的探讨p16蛋白在宫颈癌组织中的表达情况及其与患者临床特征和预后的关系。方法采用免疫组织化学染色法检测116例宫颈癌患者的宫颈癌组织标本和100例子宫肌瘤患者的正常宫颈组织标本中p16蛋白的表达情况,分析宫颈癌组织中p16蛋白的阳性表达情况与宫颈癌患者临床特征和预后的关系。结果宫颈癌组织中p16蛋白的阳性表达率明显高于正常宫颈组织(P<0.01)。不同年龄、肿瘤直径、病理类型、宫颈癌分期宫颈癌患者宫颈癌组织中p16蛋白的阳性表达率比较,差异均无统计学意义(P﹥0.05);分化程度为低分化、有淋巴结转移宫颈癌患者宫颈癌组织中p16蛋白的阳性表达率均高于分化程度为中高分化、无淋巴结转移的宫颈癌患者,差异均有统计学意义(P<0.05)。Log-rank检验结果显示,p16蛋白阴性表达患者的生存情况优于p16蛋白阳性表达患者(P<0.05)。结论低分化、有淋巴结转移宫颈癌患者宫颈癌组织中p16蛋白的阳性表达率较高,且p16蛋白阴性表达宫颈癌患者的生存情况更优。     

Caveolin-1 expression is associated with a basal-like phenotype in sporadic and hereditary breast cancer

Summary The role of caveolin 1 (CAV1), a structural component of caveolae in breast cancer is controversial, although most studies suggest that it functions as a tumor-suppressor gene. In addition, some studies have identified CAV1 as a marker of myoepithelial cells. Since myoepithelial markers are frequently expressed in breast carcinomas with a basal-like phenotype, which are frequently occurring tumors in women with BRCA1 germline mutations, we evaluated whether CAV1 was associated with a basal-like phenotype in 509 sporadic and 47 hereditary BRCA1-/BRCA2-associated carcinomas. Immunohistochemistry was performed on tissue microarrays and cases were classified as having a basal-like-phenotype if they were estrogen-receptor- and HER2-negative but cytokeratin 5/6- and/or epidermal growth factor receptor-positive. In sporadic carcinomas, CAV1 expression was found in 21 out of 496 valuable cases (4.2%). A basal-like-phenotype was found in 53 out of 498 (10.6%) cases. A strong association was found between CAV1 expression and a basal-like-phenotype, since 52% of tumors that expressed CAV1 had this phenotype, compared with only 9% of CAV1-negative carcinomas (p<0.001). CAV1 was expressed in six (12.8%) familial cases, five of which had a basal-like-phenotype (p = 0.009). Moreover, these six CAV1-positive cases were BRCA1 tumors. The difference in the frequency of CAV1 expression between BRCA1- and BRCA2-associated tumors was statistically significant (p = 0.024). In conclusion, this study reports for the first time CAV1 expression in BRCA1 and BRCA2 hereditary breast cancer and identifies CAV1 as a marker associated with a basal-like-phenotype in both hereditary and sporadic breast cancer.