乳腺癌基因甲基化的研究进展

乳腺癌的发生的分子机制仍然不明确。研究显示表观遗传学改变（Epigenetics）所导致的基因表达异常也是乳腺癌发生、发展的重要原因。表观遗传学改变是基因的核苷酸序列不发生改变的情况下基因表达的可遗传的变化,包括DNA甲基化、组蛋白乙酰化、染色质重塑、基因组印记以及非编码RNA等。乳腺腺的DNA甲基化是常见的分子事件,具有独特的DNA甲基化特征,既往的研究发现DNA甲基化可以作为乳腺癌早期诊断、分型、监测药物治疗效果和预后的分子标志物。本文将对DNA甲基化在乳腺癌的研究进展进行综述。     

A review of the alterations in DNA methylation in esophageal squamous cell carcinoma

Epigenetic changes such as DNA methylation, histone modification, and loss of genome imprinting play a crucial role in esophageal squamous cell carcinogenesis, along with genomic and genetic alterations. DNA methylation is a fundamental epigenetic process that modulates gene expression. Cancer cells exhibit two types of alterations of DNA methylation: global DNA hypomethylation and site-specific CpG island promoter hypermethylation. In several types of human cancers, the methods of detecting an aberrant methylation status have been applied to clinical fields to stratify high-risk groups, detect early cancer, and predict clinical outcomes. Importantly, epigenetic changes, including alterations in DNA methylation, are reversible and can thus be targets for cancer therapy or chemoprevention. Therefore, a better understanding of the DNA methylation in esophageal squamous cell carcinoma (ESCC) is important for optimizing cancer therapy and chemoprevention. We herein summarize the current knowledge regarding alterations in DNA methylation and the clinical implications in ESCC.     

The Loss of Estrogen and Progesterone Receptor Gene Expression in Human Breast Cancer

Hormone responsiveness is a critical determinantof breast cancer progression and management, and theresponse to endocrine therapy is highly correlated withthe estrogen receptor (ER)³ and progesterone receptor (PR) status of tumor cells. Thus, keyareas of study in breast cancer are those mechanismsthat regulate ER and PR expression in normal andmalignant breast tissues. One-third of all breastcancers lack ER and PR; these conditions are associatedwith less differentiated tumors and poorer clinicaloutcome. In addition, approximately one-half ofER-positive tumors lack PR protein and patients withthis phenotype are less likely to respond tohormonal therapies than those whose tumors express bothreceptors. Since PR is induced by ER; its presence is amarker of a functional ER. In this review, we will discuss possible mechanisms for loss of ER andPR gene expression, especially structural changes withineach gene including deletions, polymorphisms ormethylation. Improved understanding of the pathways that lead to loss of ER and/or PR proteinsshould allow the development of better predictiveindicators as well as novel therapeutic approaches totarget these hormone-independent cancers.     

Epigenetic Regulation in Estrogen Receptor Positive Breast Cancer—Role in Treatment Response

Recent advances in breast cancer treatment have allowed increasing numbers of patients with estrogen receptor (ER) positive (+) breast cancer to receive various forms of endocrine therapy. Unfortunately, de novo and acquired resistance to endocrine therapy remains a major challenge in the clinic. A number of possible mechanisms for drug resistance have been described, which include activation of growth factor receptor pathways, overexpression of ER coactivators, and metabolic resistance due to polymorphisms in metabolizing enzymes. While many of these changes are caused by genetic alterations, there is also increasing evidence to implicate epigenetic gene regulatory mechanisms in the development of endocrine resistance. Since epigenetic modifications are easier to reverse than genetic mutations, they are appealing therapeutic targets, and thus future improvements in medical care for breast cancer patients will depend upon a better understanding of the roles epigenetic modifications play in endocrine resistance. In this review we will focus on recent advances made in the understanding of epigenetic gene regulation in estrogen response and endocrine resistance in breast cancer. We will also summarize current clinical-translational advances in epigenetic therapy, and discuss potential future clinical use of epigenetic changes as therapeutic targets, especially with respect to endocrine treatment.     

表观遗传学与乳腺癌

表观遗传学是基于非DNA序列改变而产生的基因表达的变化,与肿瘤的发生密切相关,具有可逆性和遗传性,主要包括DNA甲基化、组蛋白修饰和染色体重组,它们相互作用,影响基因表达。乳腺癌中,表观遗传调节改变了一些重要基因的表达,导致了肿瘤的产生和发展。表观遗传学的研究对乳腺癌的发生、发展、早期诊断、预后评估、治疗和复发监测产生了深远的影响。     

Steroid Hormone Receptor Profile of Normal, Benign, and Malignant Female Breast Epithelium: An Immunohistochemical Analysis of 325 Biopsies

Abstract: The steroid hormone receptor (SR) profile was determined for both the estrogen receptor (ER) and progesterone receptor (PR) in 55 fibroadenomas, 69 fibrocystic changes, 38 ordinary, and 14 atypical intraductal hyperplasias as well as 149 breast carcinomas obtained from 325 female patients by diagnostic surgical biopsy. Normal breast tissue adjacent to the lesions under study was simultaneously evaluated in 234 cases. SR were proven immunohistochemically in cryostat sections using an immunohistochemical assay with rat monoclonal antibodies against human ER or PR. The findings were scored and summarized into the phenotypes ER+PR+,ER?PR+, ER+PR? and ER?PR?. The ER+PR+ status was most often found in fibroadenomas (67%) and normal breast tissue (64%) as well as in fibrocystic changes (63%) and breast carcinomas (58%). ER?PR? was inversely rare in fibroadenomas (4%), normal breast tissue (15%), fibrocystic changes (23%), and breast carcinomas (29%). The simultaneous SR analysis in breast disease and its surrounding normal tissue showed in fibroadenomas in 90% and in fibrocystic changes in 80%, a ER/PR phenotype expression similar to adjacent normal tissue; whereas in breast carcinomas the SR status corresponded with the preexisting normal tissue only in 36%. The comparative SR analysis of normal and pathological breast tissue showed a gradually inverse biological correlation between the decrease of ER+PR+ and the increase of ER?PR? frequency from benign breast changes to noninvasive and invasive breast carcinomas. In benign breast epithelium, ER?PR+ might be regarded as low-risk phenotype, whereas ER+PR? could be estimated as high-risk phenotype in view of a later dedifferentiation and possible malignization. The more frequent discordance of SR expression between breast carcinomas and their adjacent normal breast tissue suggests that the neoplastic growth may become more and more independent from normal endocrine influences.     

乳腺癌组织中AXIN2基因启动子区甲基化表达及临床意义

目的本研究旨在通过检测乳腺癌组织中AXIN2基因启动子区甲基化状态,分析其与乳腺癌相关危险因素、临床病理特征及mRNA表达间的关系,探讨其在临床应用中的价值。方法选取2018年1月至2019年12月在山东第一医科大学附属肥城市人民医院普外科经手术切除治疗的84例女性乳腺癌患者的乳腺癌组织和癌旁组织,检测组织的AXIN2基因启动子的甲基化状态和mRNA表达量,使用不同浓度的甲基转移酶抑制剂(5-Azacytidine,5-Aza)处理人乳腺癌ZR-75-1细胞,且进行乳腺癌相关危险因素和临床病理特征的收集与分析。结果乳腺癌组织的AXIN2基因启动子甲基化阳性率(40.5%)显著高于癌旁组织的甲基化阳性率(19.0%)(χ2=10.401,P=0.001)。AXIN2甲基化阳性率与乳腺癌患者的初产年龄(χ2=5.467,P=0.019)、是否有人工流产史(χ2=8.372,P=0.006)有关;AXIN2甲基化阳性率与是否发生淋巴结转移(χ2=5.338,P=0.021)、ER表达状态(χ2=9.141,P=0.002)及PR表达状态(χ2=6.918,P=0.009)有关。此外,乳腺癌组织的AXIN2基因mRNA相对表达量(00.22±0.03)显著低于癌旁组织的mRNA相对表达量(0.46±0.06)(t=3.527,P<0.001);甲基化阳性乳腺癌组织的mRNA相对表达量(0.13±0.02)显著低于甲基化阴性乳腺癌组织的mRNA相对表达量(0.29±0.04)(t=3.616,P<0.001)。ZR-75-1细胞使用5-Aza处理后,AXIN2基因mRNA相对表达量显著升高(t=3.824,P<0.001)。结论AXIN2基因启动子区DNA甲基化与乳腺癌发生机制有关,在临床中有一定应用价值。     

表观遗传学与乳腺癌

表观遗传学是基于非DNA序列改变而产生的基因表达的变化,与肿瘤的发生密切相关,具有可逆性和遗传性,主要包括DNA甲基化、组蛋白修饰和染色体重组,它们相互作用,影响基因表达.乳腺癌中,表观遗传调节改变了一些重要基因的表达,导致了肿瘤的产生和发展.表观遗传学的研究对乳腺癌的发生、发展、早期诊断、预后评估、治疗和复发监测产生了深远的影响.     

Epigenetic alterations and their clinical implications in esophageal squamous cell carcinoma

Alterations in the regulation of gene expression that do not involve a change in the DNA sequence have been increasingly recognized as an important key event of carcinogenesis, referred to as “epigenetic” changes. Major epigenetic mechanisms include the methylation of cytosines in DNA, changes of histone and chromatin structure by covalent posttranslational modifications of histone proteins and alterations in the expression of microRNAs. These epigenetic alterations have also been identified in esophageal squamous cell carcinoma (ESCC). In this brief review, we will discuss DNA hypermethylation of the tumor suppressor gene promoters, histone modifications including histone acetylation/deacetylation and histone methylation and microRNAs in ESCC. Clinical implications of these epigenetic alterations in ESCC will be also discussed.     

双侧原发性乳腺癌的多种相关癌基因与雌、孕激素受体的表达及其临床意义

目的探讨双侧原发性乳腺癌癌基因Her-2、p53、nm23及其雌激素受体(ER)、孕激素受体(PR)的表达情况,了解双侧原发性乳腺癌的生物学行为。方法研究分析20例双侧原发性乳腺癌相关癌基因Her-2、p53、nm23及其ER、PR表达情况,并与同期单侧乳腺癌比较。结果在同期650例乳腺癌中,双侧原发性乳腺癌20例,占3.07%,第一癌的ER、PR阳性率分别为60%和50%,第二癌的ER、PR阳性率分别为50%和40%,分别与同期单侧乳腺癌比较差异无统计学意义(P>0.05),第一和第二癌Her-2阳性表达率分别为40%(8/20)和30%(6/20);p53的阳性表达率分别为40%(8/20)和40%(8/20);nm23的阳性表达率分别为60%(12/20)和60%(12/20),它们与同期单侧乳腺癌比较差异均无统计学意义(P>0.05)。结论双侧原发性乳腺癌的相关癌基因Her-2、p53、nm23及其ER、PR受体改变没有特异性,与单侧乳腺癌的生物学行为相仿,治疗上应采取积极治疗措施。     

Understanding the biologic mechanisms responsible for breast-cancer progression during tamoxifen or fulvestrant treatment

BACKGROUND: Dehydroepiandosterone sulfate (DHEAS) causes breast-cancer proliferation, even during tamoxifen or fulvestrant blockade. The purpose of this study was to determine possible mechanisms for this treatment failure. METHODS: T-47D cells (estrogen receptor [ER] and progesterone receptor [PR] positive) were treated with fulvestrant (10 micromol/L), tamoxifen (10 mmol/L or 0.0001 nmol/L), or vehicle and stimulated with DHEAS. Gene expression of ER, PR, insulin-like growth factor (IGF)-1 and -2, and insulin-like growth-factor binding protein (IGFBP)-1 through -4 was determined. RESULTS: ER and PR gene expression decreased by 1.3- and 4-fold with fulvestrant and DHEAS. ER expression decreased by 2.7-fold with 0.0001 nmol/L tamoxifen and DHEAS. ER and PR expression were unchanged by 10 nmol/L tamoxifen. IGF-1 and IGF-2 were not expressed. IGFBP-2 and -4 expression decreased by 1.9- and 1.6-fold after DHEAS stimulus, although this was not statistically significant. CONCLUSIONS: DHEAS exposure, even in the presence of tamoxifen and fulvestrant, induces changes in ER and PR gene expression that may be partially responsible for breast cancer progression.     

ER、PR和p53基因检测及DNA倍体分析对结直肠癌预后判断的意义

目的 探讨ER、PR表达和p53基因检测及DNA倍体对结直肠癌预后判断的意义.方法 采用RBA 法、免疫组织化学方法和流式细胞术对286例结直肠癌标本分别进行ER、PR表达和p53基因检测及DNA倍体分析并结合患者的临床资料进行分析.结果 ER、PR表达和p53基因检测及DNA倍体分析与结直肠癌患者预后均有明显相关,差异有极显著性意义(P<0.01).DNA二倍体、p53基因检测和ER、PR的表达水平越强其患者预后越好.结论 结直肠癌ER、PR表达和p53基因检测及DNA倍体分析有助于结直肠癌患者的临床诊断及预后评估.     

凋亡相关基因 bcl-2、bax、bad与乳腺癌

目的探讨乳腺癌发生、发展过程中bcl-2、bax及bad基因表达水平变化及与乳腺癌其他生物因素的相关性。方法复习国内、外相关文献并进行综述。结果在从正常乳腺组织到乳腺癌逐渐演化的过程中凋亡抑制基因bcl-2的表达水平变化尚有待进一步研究,而凋亡促进基因bax、bad的表达水平呈递减趋势。bcl-2基因表达水平与乳腺癌中一些公认的正性因子如雌激素受体(ER)、孕激素受体(PR)呈正相关,与其他一些负性因子如p53、表皮生长因子受体、c-erbB-2、腋窝淋巴结转移情况等呈负相关。bax基因的表达水平与乳腺癌ER、PR水平以及p53表达水平等无关。对于bad基因与乳腺癌其他生物因素的相关性尚未见报道。结论乳腺癌中bcl-2基因表达水平的变化对乳腺癌预后以及治疗的作用尚存在争议,bad基因与乳腺癌预后的关系亦不清楚,而bax基因表达水平与乳腺癌的预后呈正相关。对于它们的研究将为我们评价乳腺癌的预后提供新的指标,为乳腺癌的治疗开辟新的思路。     

乳腺癌中bcl-2蛋白表达的意义

为探讨抑凋亡基因ｂｃｌ－２蛋白表达在乳腺癌中的意义,应用免疫组织化学的方法,对１２５例浸润性乳腺癌患者的石蜡包埋组织切片中ｂｃｌ－２,雌激素受体,孕激素受体及ｐ＾５３基因的表达产物进行检测。结果：ｂｃｌ－２蛋白在浸润性导管癌中的表达为６３．３％,而在浸润性小叶癌中为８８．９％,二者间菜显著性间谍;在浸润性导管癌中,ｂｃｌ－２蛋白的表达与原发癌大小及肿瘤分级呈负相关,与ＥＲ,ＰＲ的表达呈正相关,与ｐ     

Epigenetics in prostate cancer: biologic and clinical relevance

Context

Prostate cancer (PCa) is one of the most common human malignancies and arises through genetic and epigenetic alterations. Epigenetic modifications include DNA methylation, histone modifications, and microRNAs (miRNA) and produce heritable changes in gene expression without altering the DNA coding sequence.

Objective

To review progress in the understanding of PCa epigenetics and to focus upon translational applications of this knowledge.

Evidence acquisition

PubMed was searched for publications regarding PCa and DNA methylation, histone modifications, and miRNAs. Reports were selected based on the detail of analysis, mechanistic support of data, novelty, and potential clinical applications.

Evidence synthesis

Aberrant DNA methylation (hypo- and hypermethylation) is the best-characterized alteration in PCa and leads to genomic instability and inappropriate gene expression. Global and locus-specific changes in chromatin remodeling are implicated in PCa, with evidence suggesting a causative dysfunction of histone-modifying enzymes. MicroRNA deregulation also contributes to prostate carcinogenesis, including interference with androgen receptor signaling and apoptosis. There are important connections between common genetic alterations (eg, E twenty-six fusion genes) and the altered epigenetic landscape. Owing to the ubiquitous nature of epigenetic alterations, they provide potential biomarkers for PCa detection, diagnosis, assessment of prognosis, and post-treatment surveillance.

Conclusions

Altered epigenetic gene regulation is involved in the genesis and progression of PCa. Epigenetic alterations may provide valuable tools for the management of PCa patients and be targeted by pharmacologic compounds that reverse their nature. The potential for epigenetic changes in PCa requires further exploration and validation to enable translation to the clinic.     

生长抑素受体和雌激素受体在原发性乳腺癌中的表达及其意义

目的研究生长抑素受体(SSTR)与雌激素受体(ER)、孕激素受体(PR)在原发性乳腺癌中的表达及其意义。方法 采用免疫组织化学链霉菌抗生物素蛋白-过氧化酶(SP)法检测SSTR和ER、PR在68例乳腺癌中的表达。结果 在68例乳腺癌中,SSTR阳性表达44例(64.70％),ER、PR阳性表达51例(75.70％),ER、PR和SSTR同时阳性表达阳性41例(60.29％)。ER、PR和SSTR两者表达呈正相关(r=0.651 6,P<0.05)。SSTR阳性患者复发率和死亡率低于SSTR阴性者(P<0.05);SSTR阳性且ER、PR阳性患者复发率和死亡率明显低于SSTR阴性ER、PR阴性患者(P<0.01)。病理分化低的有47例,SSTR阳性表达36例(P>0.05)。结论SSTR表达与ER、PR表达有明显相关性,有可能作为判断乳腺癌预后的指标。