Jagged1基因甲基化与乳腺癌发生发展相关性探讨

目的 探讨Jagged1基因异常甲基化在乳腺癌发生发展过程中的意义.方法 采用MALDI-TOF MS法检测2004-01-16-2009-06-25石河子大学第一附属医院63例乳腺浸润性导管癌(invasive ductal carcinoma,IDC)、20例导管原位癌(ductal carcinoma in situ,DCIS)、20例非典型导管增生(atypical ductal hyperplasia,ADH)和20例普通型导管增生(usual ductal hyperplasia,UDH)组织中Jagged1基因甲基化水平,免疫组织化学方法检测4组乳腺组织中Jagged1蛋白表达状况,在IDC组中进一步分析Jagged1甲基化和表达与临床病理特征的相关性.结果 Jagged1基因总甲基化率在IDC(0.127 6±0.067 5)、DCIS(0.138 9±0.093 1)、ADH(0.168 0±0.014 6)和UDH(0.223 3±0.060 9)中逐渐升高,并且IDC组甲基化率分别与ADH(P=0.015)和UDH(P＜0.001)组比较,差异有统计学意义.CpG-2、CpG-6、CpG-13、CpG-20.21.22、CpG-23.24.25、CpG-26位点的甲基化率在IDC组最低,差异有统计学意义,P值均＜0.05.Jagged1蛋白在IDC(58.7％,37/63)、DCIS(45.0％,9/20)、ADH(40.0％,8/20)和UDH(25.0％,4/20)组中阳性表达率逐渐降低,其中IDC组的阳性率显著高于UDH组,P=0.003.Jagged1蛋白高表达与DNA低甲基化在IDC(P＜0.001)、DCIS(P=0.003)、ADH(P=0.004)和UDH组(P=0.007)均有相关性.Jagged1基因低甲基化和蛋白高表达与临床分期(P＜0.001;P=0.019)和组织学分级(P=0.003;P=0.025)均有相关性.结论 Jagged1基因低甲基化和CpG位点低甲基化,可能参与乳腺癌的发生,并且Jagged1基因低甲基化可能是调控蛋白高表达的方式之一,进而促进乳腺的癌变和进展.     

60例乳腺癌术后远处转移临床分析

目的 探讨乳腺癌术后远处转移的临床病程及合理综合治疗的重要性。方法 共收治乳腺癌术后远处转移病人60例,初治时Ⅰ期18例,Ⅱ期33例,Ⅲ期9例,全部施行根治性手术,Ⅰ、Ⅱ期患者术后化疗1－2个周期者21例,术后放疗者18例,另12例未行化、放疗、Ⅲ期患者术后予放疗。总结初始治疗后出现转移的时间。结果 60例病人在初次治疗后1－6年发生了远处转移。结论 乳腺癌是好发血行转移的恶性肿瘤、合理综合是提高治愈率的关键。     

60例乳腺癌术后远处转移临床分析

目的　探讨乳腺癌术后远处转移的临床病程及合理综合治疗的重要性。方法　共收治乳腺癌术后远处转移病人 6 0例 ,初治时Ⅰ期 18例 ,Ⅱ期 3 3例 ,Ⅲ期 9例 ,全部施行根治性手术 ,Ⅰ、Ⅱ期患者术后化疗 1～ 2个周期者 2 1例 ,术后放疗者 18例 ,另 12例未行化、放疗 ,Ⅲ期患者术后给予放疗。总结初次治疗后出现转移的时间。结果　 6 0例病人在初次治疗后 1～ 6年发生了远处转移。结论　乳腺癌是好发血行转移的恶性肿瘤 ,合理综合治疗是提高治愈率的关键     

乳腺癌延期根治术对远处转移的影响

目的　探讨乳腺癌延期根治术对远处转移的影响。方法　收集 1989年 1月至 1993年 12月行根治术后 ,在本科接受放疗的乳腺癌患者 2 3 6例 ,其中延期根治术的 49例 (治疗组 ) ;一次性根治术的 187例 (对照组 ) ;两组病例随访时间超过 5年。对两组病例的远处转移采用 χ2 检验比较分析。结果　治疗组远处转移 2 9例 ( 5 9 2 % ) ;对照组远处转移 5 7例 ( 3 0 5 % ) ;两组比较差异具有显著性(P <0 0 5 )。结论　延期根治术可增加乳腺癌远处转移的危险性。     

乳腺癌术后放疗后远处转移若干因素探讨

乳腺癌治疗失败主要原因是远处转移。我科自1976年～1985年共收治女性单侧乳腺癌术后补充放疗的共696例,均经术后病理证实,随访1～12年。出现远处转移的共153例,其中肺转移94例,依次是骨、脑、肝的转移。乳腺癌出现远处转移,即占治疗失败病例中2/3。而从本组病例中看出乳腺癌的国际分期、患者年令、肿瘤大小和腋淋巴结常规病理检查有无转移及转移数目多少,对预后影响极大。     

BRMS1抗肿瘤转移作用及其机制研究进展

自乳腺癌转移抑制基因1（BRMS1）被发现以来,人们已经对其基因定位、序列组成、空间结构和生物学功能等方面有了一定的认识．近年来更发现BRMS1与除乳腺癌外的其他恶性肿瘤如卯巢癌、子宫内膜癌、胃癌等的转移也有相关性。文章对BRMS1在多种肿瘤中的表达、作用及其机制研究现状了以介绍。     

nm23基因在乳腺癌中的表达及与远处转移相关性的研究

应用免疫组化方法，对１０１例有８年随访结果的乳腺癌病例，进行了ｎｍ２３基因蛋白表达的检测。结果显示，ｎｍ２３基因蛋白表达与血行转移、淋巴结转移的发生呈负相关，与其它临床指标无关。生存率分析表明：ｎｍ２３基因高表达组患者的生存率明显高于低表达组（Ｐ＜０．０５）；腋淋巴结阴性组中，ｎｍ２３基因高、低表达的患者生存率差别显著，提示若将腋淋巴结阴性组中具有潜在转移危险性的ｎｍ２３低表达患者筛选出来，加强治疗，将会有助于提高生存率。应用Ｃｏｘ比例风险模型进行的多因素分析显示，ｎｍ２３基因表达与腋淋巴结转移、肿瘤大小均为乳腺癌的预后因素，其中ｎｍ２３基因高表达患者死亡的相对危险度较低表达患者低５４％。本研究结果提示，ｎｍ２３基因表达可以作为一项独立的预后指标，用以指导乳腺癌的临床治疗。     

舌癌远处转移的研究

本文报告了舌癌远处转移的研究，论述了血道扩散与转移的关系，提出了减少远处转移的方法，在１８８例舌癌患者中有１０例远处转移的患者，其中包括了７例肺转移及３例肝转移，肺转移为肝转移的２．３倍。此１０例患者为鳞状上皮癌，腺癌，未分化癌，分化程度谐为Ⅲ￣Ⅳ级，说明病理分级与远处转移有重要关系。     

血脂与激素受体阴性乳腺癌远处转移及疗效的关系

目的 测定激素受体阴性乳腺癌患者的血脂水平,探讨血脂异常与远处转移的关系,及化疗后血脂水平变化与近期疗效的关系。方法 收集154例激素受体阴性乳腺癌患者的临床病理资料和空腹血脂水平,远处转移组患者化疗2周期后第14天再次测定血脂水平。χ²检验分析临床病理特征及基线血脂水平与远处转移的关系,Logistic回归分析远处转移的独立危险因素,配对t检验分析远处转移组患者化疗后血脂各指标变化与疗效关系。结果 乳腺癌远处转移与肿块大小、区域淋巴结转移、组织学分级、高TC、高TG及高LDL-C血症有关(P＜0.05)。Logistic回归分析显示,肿块大小(OR=1.563)、区域淋巴结转移(OR=1.983)、高TC血症(OR=1.502)、高TG血症(OR=1.877)是远处转移的独立危险因素。远处转移组中化疗有效组(PR+SD),TC、TG及LDL-C水平有降低趋势,HDL-C水平有升高趋势,疗效PR组TG水平降低有统计学意义。结论 高脂血症与激素受体阴性乳腺癌远处转移相关,有效的抗肿瘤治疗可降低血脂水平。动态监测血脂水平可作为激素受体阴性乳腺癌远处转移及疗效评价的辅助参考指标。     

乳腺癌肺转移机制及治疗进展

肺部是晚期乳腺癌的常见转移部位,肺转移可能引起咳嗽、咯血、疼痛、胸腔积液和肺功能障碍等临床症状,严重影响患者的生活质量。目前关于乳腺癌肺转移治疗有局部治疗和全身治疗,但是存在肺转移的乳腺癌患者的生存率仍然很低,提高患者的疗效和延长生存时间一直是患者及医务工作者关心的热点问题。本文将对乳腺癌肺转移机制及肺转移最新治疗进展进行综述,以期为乳腺癌肺转移患者临床治疗提供新思路。     

Locoregional and distant recurrences after breast conserving therapy in patients with triple-negative breast cancer: A meta-analysis

BackgroundWith higher incidence of recurrence, ongoing dispute exists on whether triple-negative breast cancer (TNBC) is a good candidate for breast conserving therapy (BCT).ObjectiveWe aimed to appraise the safety of BCT in treating TNBC, in comparison with modified radical mastectomy. The prognostic effect of TN phenotype in conservatively managed patients was also assessed.MethodsA systematic search for studies regarding recurrences in patients with TNBC or treated by BCT was conducted up to March 2013. Summary relative risks (RRs) for ipsilateral locoregional recurrence (ILRR) and distant metastasis (DM) were calculated in a fixed-effects model.ResultsTwenty-two studies concerning 15,312 breast cancer patients were analyzed. In the cohort of TNBC, the patients receiving BCT were less likely to develop ILRR and DM in comparison with mastectomy (RR 0.75, 95% CI 0.65–0.87; RR 0.68, 95% CI 0.60–0.76). In the cohort of BCT, the TN subtype increased the risks of both ILRR and DM than non-TN subtypes (RR 1.88, 95% CI 1.58–2.22; RR 2.12, 95% CI 1.72–2.62). Further subgroup analyses of BCT cohort revealed that the luminal phenotype had the most favorable prognosis. Notably, TN subtype was less likely to develop ILRR than HER-2 subtype (RR 0.69, 95% CI 0.53–0.91), there was no difference in DM rate between them.ConclusionsBCT benefits patients with TNBC than mastectomy does. However, TN subtype predicts a poorer prognosis than non-TN subtype, suggesting more aggressive adjuvant therapy for TNBC be established in future trials.     

Reducing the risk of distant metastases in breast cancer patients: role of aromatase inhibitors

Breast cancer continues to be one of the most prominent causes of cancer death among women worldwide. Mortality in breast cancer is most commonly caused by the occurrence of distant metastases. Thus, treatments that reduce the risk of distant metastases are likely to improve survival. The third-generation aromatase inhibitors (AIs), including anastrozole, letrozole, and exemestane, have been investigated as alternatives to tamoxifen for the adjuvant treatment of early, endocrine-responsive breast cancer. Results from several large trials have established the superior efficacy of the AIs over tamoxifen in reducing the risk of recurrences when used as upfront, switch, and extended adjuvant therapy. Here, we review recent updated results obtained with AIs as adjuvant therapy, in terms of reducing the risk of distant metastases.     

microRNAs in breast cancer development and treatment

microRNAs (herein after miRNAs) represent a recently uncovered class of small and endogenous non-coding RNAs. miRNAs play a well conserved and crucial role in normal biological processes, such as cell differentiation, proliferation and apoptosis through a complicated gene regulation networking. The recent rise of interest in miRNAs in cancer research is ascribed to the breakthrough of their role in many pathological processes, including malignant transformation. miRNAs signatures have been clearly defined for certain types of cancer, with correlation to tumor aggressiveness, therapy response and patient outcome. Furthermore, the use of miRNAs as therapeutic targets for cancer is currently under investigation. The aim of this review is to focus on the role of miRNAs in breast cancer development and to summarize the evidence for their potential diagnostic and therapeutic applications in clinical practice.     

Quantitative DNA hypomethylation of ligand Jagged1 and receptor Notch1 signifies occurrence and progression of breast carcinoma

Methylation alterations of Jagged1 and Notch1 genes have been reported in non-tumor lesions and a few cancers. However, methylation profiles of Jagged1 promoter and Notch1 exon25 in breast cancer and matched normal tissue and the association of methylation with clinicopathological characteristics still remain unclear. To explore the potential effects of aberrant DNA methylation of Jagged1 and Notch1 on occurrence and progression of breast cancer, we detected the quantitative DNA methylation of Jagged1 and Notch1 in 73 breast cancer (BC) and 20 adjacent normal breast tissues (ANBT) by using MassARRAY spectrometry. The methylation level of overall and majority individual CpG sites of the two genes were synergistically significantly lower in BC than in ANBT. The overall hypomethylation of the two genes, particularly of Jagged1 CpG_8.9.10 and Notch1 CpG_14.15.16 in primary tumors, were markedly associated with lymph node metastasis, advanced stage and high grade. The protein expressions of the both genes were examined by immunohistochemical staining in same cohorts. The expression was significantly inverse correlation with methylation. The two proteins in primary tumor were synergistically up-regulated and dramatically related to lymph node metastasis, advanced stage and high grade. Our findings suggest that the synergetic hypomethylation of Jagged1 and Notch1 genes, especially of Jagged1 CpG_8.9.10 and Notch1 CpG_14.15.16, may involve tumorigenesis and development of breast cancer. The negative relationship between methylation and expression indicates methylation role for expression regulation. The synergetic overexpression of the two proteins further indicates the effects on occurrence and progression of breast cancer.     

Quantitative DNA hypomethylation of ligand Jagged1 and receptor Notch1 signifies occurrence and progression of breast carcinoma

Methylation alterations of Jagged1 and Notch1 genes have been reported in non-tumor lesions and a few cancers. However, methylation profiles of Jagged1 promoter and Notch1 exon25 in breast cancer and matched normal tissue and the association of methylation with clinicopathological characteristics still remain unclear. To explore the potential effects of aberrant DNA methylation of Jagged1 and Notch1 on occurrence and progression of breast cancer, we detected the quantitative DNA methylation of Jagged1 and Notch1 in 73 breast cancer (BC) and 20 adjacent normal breast tissues (ANBT) by using MassARRAY spectrometry. The methylation level of overall and majority individual CpG sites of the two genes were synergistically significantly lower in BC than in ANBT. The overall hypomethylation of the two genes, particularly of Jagged1 CpG_8.9.10 and Notch1 CpG_14.15.16 in primary tumors, were markedly associated with lymph node metastasis, advanced stage and high grade. The protein expressions of the both genes were examined by immunohistochemical staining in same cohorts. The expression was significantly inverse correlation with methylation. The two proteins in primary tumor were synergistically up-regulated and dramatically related to lymph node metastasis, advanced stage and high grade. Our findings suggest that the synergetic hypomethylation of Jagged1 and Notch1 genes, especially of Jagged1 CpG_8.9.10 and Notch1 CpG_14.15.16, may involve tumorigenesis and development of breast cancer. The negative relationship between methylation and expression indicates methylation role for expression regulation. The synergetic overexpression of the two proteins further indicates the effects on occurrence and progression of breast cancer.     

A case of breast cancer diagnosed by inguinal lymph node metastasis

We describe a case of a 58-year-old woman with right inguinal lymph node swelling and a T1 tumor in the right breast. She was referred with an 18-month history of the former complaint and a six-month history of the latter. Excisional biopsy of the inguinal lymph node revealed breast cancer metastasis. Radiographical examination showed no metastases to the lungs, liver or bone. Modified radical mastectomy was performed. Histological examination revealed solid tubular carcinoma, PT2, PM (axillary lymph node metastases 4/16), stage IV. Estrogen and progesterone receptors were negative. Three cycles of postoperative cyclophosphamide, adriamycin and 5-fluorouracil (CAF) chemotherapy were given, and the right inguinal area was irradiated with 40 Gy. The patient complained of swelling in both legs three years after surgery. Computed tomography revealed marked lymph node swellings in the pelvic cavity. She died six months later. Inguinal lymph node metastasis from breast cancer is very rare, although distant lymph node metastasis in the cervix occurs frequently. This case should help clarify how breast cancer metastasizes to distant lymph nodes.     

乳腺癌转移抑制基因1抑制肿瘤转移的作用机制

乳腺癌转移抑制基因1 (BRMS1)在多种恶性肿瘤细胞中表达降低或缺失,具有明显降低癌细胞侵袭和转移的作用.BRMS1基因通过磷酸肌醇信号及核转录因子-κB(NF-κB)信号通路等调节基因转录和蛋白翻译,还可与mSin3-组蛋白去乙酰化酶(HDAC)复合体、雌激素受体等蛋白相互作用、修复细胞间隙通讯等途径抑制肿瘤细胞的侵袭及转移.BRMS1基因将可能成为有效抑制肿瘤转移基因治疗的新靶点.     

Exosomes in development,metastasis and drug resistance of breast cancer

Transport through the cell membrane can be divided into active, passive and vesicular types (exosomes). Exosomes are nano‐sized vesicles released by a variety of cells. Emerging evidence shows that exosomes play a critical role in cancers. Exosomes mediate communication between stroma and cancer cells through the transfer of nucleic acid and proteins. It is demonstrated that the contents and the quantity of exosomes will change after occurrence of cancers. Over the last decade, growing attention has been paid to the role of exosomes in the development of breast cancer, the most life‐threatening cancer in women. Breast cancer could induce salivary glands to secret specific exosomes, which could be used as biomarkers in the diagnosis of early breast cancer. Exosome‐delivered nucleic acid and proteins partly facilitate the tumorigenesis, metastasis and resistance of breast cancer. Exosomes could also transmit anti‐cancer drugs outside breast cancer cells, therefore leading to drug resistance. However, exosomes are effective tools for transportation of anti‐cancer drugs with lower immunogenicity and toxicity. This is a promising way to establish a drug delivery system.