乳腺癌中激活轉錄因子6β的表達變化與預后的相關性

乳腺癌中激活轉錄因子6β的表達變化與預后的相關性【摘要】目的分析激活轉錄因子6β（activatingtranscriptionfactor6beta，ATF6β/ATF6B）在乳腺癌中表達的改變及表達改變對于乳腺癌預后的意義。方法使用cBioPortal數據平臺訪問最新TCGA浸潤性乳腺癌數據集，分析ATF6β基因錯義突變、基因擴增、mRNA水平變化、mRNA高表達與預后的關系，以及基因甲基化水平和ATF6β表達水平的關系；使用Oncomine數據平臺分析乳腺癌組織與癌旁組織中ATF6β基因表達的差異性；使用多組學數據分析門戶網站LinkedOmics分析浸潤性乳腺癌組織中ATF6β基因表達變化與臨床各項指標的相關性。結果cBioPortal分析結果顯示，13%（142/1093）乳腺癌患者發(fā)生ATF6β基因改變，改變類型包括基因擴增、錯義突變和mRNA水平改變，其中ATF6βmRNA水平上調占總樣本量的9%，進一步分析結果顯示mRNA水平上調不利于患者預后（P<0.01）；ATF6β水平與其基因拷貝數變化呈正相關（P<0.01，相關系數=0.45），與其基因甲基化水平呈負相關（P<0.01，相關系數=-0.28）；Oncomine結果顯示乳腺癌組織中ATF6β基因表達水平顯著高于正常乳腺組織（P<0.01）；LinkedOmics結果顯示浸潤性乳腺癌患者中ATF6β表達水平分別受PAM50分子分型和腫瘤純度（P<0.01；P<0.01）。結論乳腺癌中ATF6β基因拷貝數增加和低甲基化促進其高表達，DHX16高表達不利于乳腺癌預后，可作為乳腺癌預后的潛在標志物?！娟P鍵詞】乳腺癌；ATF6β；預后；拷貝數變化；甲基化Therelationshipbetweentheexpressionofactivatortranscriptionfactor6betaandprognosisinbreastcancer【Abstract】ObjectiveTostudythetranscriptionallevelofATF6βmRNAinbreastcancertissue,andtodeterminewhetherthehighexpressionisrelatedtotheoccurrence,developmentandprognosisofbreastcancer.MethodsUsetheDataplatformofcBioPortaltovisitTCGAdatabaseandcollectdatasetofinvasivebreastcancer,analyzetherelationshipbetweenmutation,changeofcopies,themRNAoverexpressionandclinicalprognosisofATF6βgene;besidesthechangeofcopiesandmethylationleveleffectonmRNAexpression.UseOncominetoanalyzethedifferentofATF6βgeneexpressionbetweenbreastcancertissueandparacanceroustissues;Useportalsiteofmulti-omicsdataanalyzewebsiteLinkOmicstoresearchtherelevancebetweenATF6βgenemRNAexpressionlevelandvariousclinicalindicators.ResultscBioPortalanalysisresultsshowedthatamong1093invasivebreastcancerpatients,13%werefoundATF6βgenechange,includingmutation,changeofcopies,mRNAexpressionlevelupgraded,anddowngraded,numberoftheATF6βgenemRNAlevelupgradedoccupied9%ofallsamples,furthermoretheupgradeofwhichisdetrimentaltotheprognosis(P＜0.01).TheATF6βgenemRNAlevelwascorrelatedpositivelywithitsgenecopies(P＜0.01),andpositivelywithitsmethylationlevel(P＜0.01).TheOncomineanalysisresultsshowedthattheATF6βgenemRNAlevelinparacanceroustissuewassignificantlowerthanthatofpatientswithbreastcancer(P＜0.01);LinkedOmicsanalysisresultsshowedthattheATF6βgenemRNAlevelwassignificantlyeffectedbyPAM50typing(Her2,LumA,LumB),raceandhistologytyping(P＜0.01;P＜0.01;P＜0.01;P＜0.01;P＜0.01).ConclusionsBreastcancerrelatedgeneATF6Βgenecopynumberincreaseandmethylationmodificationleadtohighexpressionofthegeneinbreastcancertissue.Thehighexpressionofthisgeneiscloselyrelatedtotheprognosisofbreastcancer.SuggestingATF6βgenemRNAcanbeusedasaspecifictumormarker,providingnewideasforthediagnosisandtreatmentofbreastcancer.【Keywords】Breastcancer;ATF6β;Prognosis;Copynumbervariation;Methylation乳腺癌（Breastcancer）是全世界女性最常見的惡性腫瘤，近年來我國乳腺癌發(fā)病率呈明顯上升趨勢ADDINEN.CITE<EndNote><Cite><Author>Ghoncheh</Author><Year>2016</Year><RecNum>166</RecNum><DisplayText>[1]</DisplayText><record><rec-number>166</rec-number><foreign-keys><keyapp="EN"db-id="er0dptdx5w0ff5e2rr4x0528xvpw2dp0ad25"timestamp="1524720776">166</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Ghoncheh,Mahshid</author><author>Pournamdar,Zahra</author><author>Salehiniya</author></authors></contributors><titles><title>IncidenceandMortalityandEpidemiologyofBreastCancerintheWorld</title><secondary-title>AsianPacificJournalofCancerPrevention</secondary-title></titles><periodical><full-title>AsianPacificJournalofCancerPrevention</full-title></periodical><pages>43-46</pages><volume>17</volume><number>sup3</number><dates><year>2016</year></dates><isbn>1513-7368</isbn><urls></urls><electronic-resource-num>10.7314/apjcp.2016.17.s3.43</electronic-resource-num></record></Cite></EndNote>[1]。據最新的統(tǒng)計，中國的年乳腺癌發(fā)病例數占世界總新發(fā)病數的12.2%，且每年因乳腺癌死亡的病例數占世界總數的9.6%ADDINEN.CITE<EndNote><Cite><RecNum>73</RecNum><DisplayText>[2]</DisplayText><record><rec-number>73</rec-number><foreign-keys><keyapp="EN"db-id="er0dptdx5w0ff5e2rr4x0528xvpw2dp0ad25"timestamp="1521036336">73</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>LeiFan,KathrinStrasser-Weippl,Jun-JieLi</author></authors></contributors><titles><title>BreastcancerinChina</title><secondary-title>LancetOncol,2014;15:e279–89</secondary-title></titles><periodical><full-title>LancetOncol,2014;15:e279–89</full-title></periodical><dates><year>2014</year></dates><urls><related-urls><url>/journals/lanonc/article/PIIS1470-2045(13)70567-9/fulltext</url></related-urls></urls><electronic-resource-num>10.1016/S1470-2045(13)70567-9</electronic-resource-num></record></Cite></EndNote>[2]。ATF6β是一種蛋白質編碼基因，其編碼的基因主要參與內質網應激反應。研究發(fā)現(xiàn)ATF6β通過參與內質網應激提高腫瘤細胞中的炎性反應和細胞壞死過程ADDINEN.CITEADDINEN.CITE.DATA[3,4]。另有研究報道肺內皮細胞中未折疊或錯誤折疊蛋白質導致的內質網應激或內質網應激引起的凋亡參與了慢性阻塞性肺疾病的發(fā)生；酸性引起的內吞則會通過引起內質網應激而保護肺癌細胞ADDINEN.CITE<EndNote><Cite><Author>Xie</Author><Year>2015</Year><RecNum>11</RecNum><DisplayText>[5]</DisplayText><record><rec-number>11</rec-number><foreign-keys><keyapp="EN"db-id="rre2xxpar5fzvmef0w8vsw2o529tzzv2zt5t"timestamp="1521686554">11</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Xie,Wen-Yue</author><author>Zhou,Xiang-Dong</author><author>Li,Qi</author><author>Chen,Ling-Xiu</author><author>Ran,Dan-Hua</author></authors></contributors><titles><title>Acid-inducedautophagyprotectshumanlungcancercellsfromapoptosisbyactivatingERstress</title><secondary-title>ExperimentalCellResearch</secondary-title></titles><periodical><full-title>ExperimentalCellResearch</full-title></periodical><pages>270-279</pages><volume>339</volume><number>2</number><keywords><keyword>Tumormicroenvironment</keyword><keyword>Acid</keyword><keyword>Autophagy</keyword><keyword>Lungcancer</keyword><keyword>ERstress</keyword><keyword>Apoptosis</keyword></keywords><dates><year>2015</year><pub-dates><date>2015/12/10/</date></pub-dates></dates><isbn>0014-4827</isbn><urls><related-urls><url>/science/article/pii/S0014482715301488</url></related-urls></urls><electronic-resource-num>/10.1016/j.yexcr.2015.11.005</electronic-resource-num></record></Cite></EndNote>[5]。但是，ATF6β在乳腺癌發(fā)生與發(fā)展過程中的研究未見報道。本文利用多組學高通量數據分析ATF6β在乳腺癌中的表達及臨床意義。材料和方法1．數據來源本研究通過癌癥基因組學分析網站cBioPortalADDINEN.CITEADDINEN.CITE.DATA[6,7]（/）、癌癥芯片數據庫OncomineADDINEN.CITE<EndNote><Cite><RecNum>56</RecNum><DisplayText>[8]</DisplayText><record><rec-number>56</rec-number><foreign-keys><keyapp="EN"db-id="er0dptdx5w0ff5e2rr4x0528xvpw2dp0ad25"timestamp="1520922020">56</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>DanielR.Rhodes*,y,2,JianjunYu*,y,2,K.Shankerz</author></authors></contributors><titles><title>ONCOMINE:ACancerMicroarrayDatabaseandIntegratedData-MiningPlatform</title><secondary-title>Neoplasia.Vol.6,No.1,January/February2004,pp.1–6</secondary-title></titles><periodical><full-title>Neoplasia.Vol.6,No.1,January/February2004,pp.1–6</full-title></periodical><dates></dates><urls></urls></record></Cite></EndNote>[8]（/resource/main.html）、癌癥多組學分析數據平臺LinkedOmicsADDINEN.CITE<EndNote><Cite><Author>Vasaikar</Author><Year>2018</Year><RecNum>57</RecNum><DisplayText>[9]</DisplayText><record><rec-number>57</rec-number><foreign-keys><keyapp="EN"db-id="er0dptdx5w0ff5e2rr4x0528xvpw2dp0ad25"timestamp="1520922817">57</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Vasaikar,S.V.</author><author>Straub,P.</author><author>Wang,J.</author><author>Zhang,B.</author></authors></contributors><auth-address>LesterandSueSmithBreastCenter,BaylorCollegeofMedicine,Houston,TX77030,USA. DepartmentofMolecularandHumanGenetics,BaylorCollegeofMedicine,Houston,TX77030,USA. DepartmentofBiomedicalInformatics,VanderbiltUniversityMedicalCenter,Nashville,TN37203,USA.</auth-address><titles><title>LinkedOmics:analyzingmulti-omicsdatawithinandacross32cancertypes</title><secondary-title>NucleicAcidsRes</secondary-title></titles><periodical><full-title>NucleicAcidsRes</full-title><abbr-1>Nucleicacidsresearch</abbr-1></periodical><pages>D956-D963</pages><volume>46</volume><number>D1</number><dates><year>2018</year><pub-dates><date>Jan4</date></pub-dates></dates><isbn>1362-4962(Electronic) 0305-1048(Linking)</isbn><accession-num>29136207</accession-num><urls><related-urls><url>/pubmed/29136207</url></related-urls></urls><custom2>PMC5753188</custom2><electronic-resource-num>10.1093/nar/gkx1090</electronic-resource-num></record></Cite></EndNote>[9]（/admin.php）分析乳腺癌組織中ATF6β基因表達的變化及臨床相關性。2．數據分析方法2.1登錄cBioPortal首頁，選擇實時更新的TCGA浸潤性乳腺癌患者數據集，分析ATF6β基因突變、拷貝數變化、mRNA水平變化以及ATF6β高表達與患者預后的關系。分析ATF6βmRNA水平發(fā)生變化時，選擇RNA測序結果，得到的分析結果直接下載；進一步分析ATF6β高表達與患者預后的關系，得到的分析結果可直接下載。另外，使用該網站分析ATF6βmRNA水平變化與ATF6β拷貝數變化及甲基化的相關性。2.2登錄Oncomine首頁，搜索框內輸入“ATF6β”，差異表達中選擇“癌癥vs正常組織”，癌癥類型選擇“乳腺癌”，閾值設置為“0.05”，數據集選擇“DuctalBreastCarcinoma(47)”其他均為默認值。結果呈現(xiàn)選擇可視化柱狀圖形式，結果可見正常乳腺組織7例，浸潤性乳腺癌40例，鼠標懸停于圖狀中的每一個結果，均可顯示ATF6βmRNA的數值，將數值輸入GraphPad軟件作圖，得到結果。2.3登錄LinkedOmics首頁，癌癥組選擇“TCGABRCA”，檢索數據集選擇“HiSeqRNA”，輸入目標基因“ATF6β”，目標數據集選擇“Clinical”，統(tǒng)計方法選擇“Non-parametricTtest”，提交，在分析結果中選擇“P<0.05”的臨床相關指標并進行下載。結果ATF6β在乳腺癌患者中表達的變化及表達變化與預后的關系：結果顯示，樣本乳腺癌患者中13%發(fā)生ATF6β基因的改變，改變類型包括基因擴增、缺失、錯義突變、mRNA水平改變（圖1-A）；進一步分析發(fā)現(xiàn)9%患者ATF6βmRNA水平上調（閾值EXP>=2）（圖1-B），且ATF6βmRNA水平上調不利于乳腺癌預后（P<0.01）（圖1-C）；乳腺癌組織中ATF6βmRNA水平較正常乳腺組織顯著上調（P<0.01）（圖1-D）。圖1A.ATF6β在乳腺癌中基因改變的情況；B.ATF6β在乳腺癌中mRNA水平上調占9%；C.乳腺癌患者中ATF6β高表達不利于患者生存；D.正常組織ATF6βmRNA拷貝數變化較浸潤性乳腺癌組織低。乳腺癌患者ATF6β基因表達變化與臨床指標相關性：結果顯示，乳腺癌患者ATF6β基因表達在不同PAM50分子亞型、腫瘤純度中表達均有差異（P<0.05,P<0.05）（圖2-A,圖2-B）。圖2ATF6β表達與PAM50分子分型和腫瘤純度的關系ATF6Β基因甲基化、mRNA拷貝數變化影響其表達：結果顯示，ATF6β拷貝數變化和ATF6β基因表達水平呈正相關（P<0.05，相關系數=0.45）（圖3-A）；ATF6β基因甲基化和ATF6β基因表達水平呈負相關（P<0.05，相關系數=-0.28）（圖3-B）。圖3A.乳腺中ATF6β基因甲基化和基因表達水平呈正相關；B.乳腺中ATF6β基因拷貝數變化和基因表達水水平呈負相關。討論乳腺癌作為中國女性患病率最高的惡性腫瘤，近年來被確診的患者數一直在增加ADDINEN.CITEADDINEN.CITE.DATA[10]。伴隨乳腺癌診斷和治療水平不斷提高，患者的生存時間和生活質量得到了改善ADDINEN.CITE<EndNote><Cite><Author>畢曄</Author><RecNum>53</RecNum><DisplayText>[11]</DisplayText><record><rec-number>53</rec-number><foreign-keys><keyapp="EN"db-id="er0dptdx5w0ff5e2rr4x0528xvpw2dp0ad25"timestamp="1520919823">53</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author><styleface="normal"font="default"charset="134"size="100%">畢曄,邊莉,黃槧</style></author></authors></contributors><titles><title><styleface="normal"font="default"charset="134"size="100%">我國乳腺癌熱點問題研究的現(xiàn)狀分析</style></title><secondary-title><styleface="normal"font="default"charset="134"size="100%">中華腫瘤防治雜志</style></secondary-title></titles><periodical><full-title>中華腫瘤防治雜志</full-title></periodical><pages>2006,13(16):1205-1211</pages><dates></dates><urls></urls></record></Cite></EndNote>[11]，但是其發(fā)病機制仍未完全得以揭示，預后標志物也難以滿足臨床需要ADDINEN.CITEADDINEN.CITE.DATA[12]。本文首次發(fā)現(xiàn)ATF6β在乳腺癌組織中高表達，提示該分子參與乳腺癌發(fā)生與進展。內質網（EndoplasmicReticulum,ER）是真核細胞中蛋白質合成后加工的重要細胞器，在一些條件下，蛋白質發(fā)生錯誤折疊，導致內質網應激（ERS）的發(fā)生ADDINEN.CITE<EndNote><Cite><Author>Liu</Author><Year>2003</Year><RecNum>15</RecNum><DisplayText>[13]</DisplayText><record><rec-number>15</rec-number><foreign-keys><keyapp="EN"db-id="rre2xxpar5fzvmef0w8vsw2o529tzzv2zt5t"timestamp="1521686720">15</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Liu,C.Y.</author><author>Kaufman,R.J.</author></authors></contributors><auth-address>HowardHughesMedicalInstitute,DepartmentofBiologicalChemistry,UniversityofMichiganMedicalSchool,AnnArbor,Michigan48109-0650,USA.</auth-address><titles><title>Theunfoldedproteinresponse</title><secondary-title>JCellSci</secondary-title><alt-title>Journalofcellscience</alt-title></titles><periodical><full-title>JCellSci</full-title><abbr-1>Journalofcellscience</abbr-1></periodical><alt-periodical><full-title>JCellSci</full-title><abbr-1>Journalofcellscience</abbr-1></alt-periodical><pages>1861-2</pages><volume>116</volume><number>Pt10</number><keywords><keyword>ActivatingTranscriptionFactor6</keyword><keyword>Animals</keyword><keyword>DNA-BindingProteins/*physiology</keyword><keyword>EndoplasmicReticulum/*metabolism</keyword><keyword>Endoribonucleases</keyword><keyword>Humans</keyword><keyword>MembraneProteins/*physiology</keyword><keyword>Models,Biological</keyword><keyword>*ProteinFolding</keyword><keyword>Protein-Serine-ThreonineKinases/*physiology</keyword><keyword>TranscriptionFactors/*physiology</keyword><keyword>Transcription,Genetic</keyword><keyword>eIF-2Kinase/*physiology</keyword></keywords><dates><year>2003</year><pub-dates><date>May15</date></pub-dates></dates><isbn>0021-9533(Print) 0021-9533(Linking)</isbn><accession-num>12692187</accession-num><urls><related-urls><url>/pubmed/12692187</url></related-urls></urls><electronic-resource-num>10.1242/jcs.00408</electronic-resource-num></record></Cite></EndNote>[13]。內質網的應激會進一步改變內質網環(huán)境并引起新合成蛋白質錯誤折疊，在這種條件下，數個以內質網為靶點基因的表達增加，以對抗此應激反應ADDINEN.CITE<EndNote><Cite><Author>Spear</Author><Year>2001</Year><RecNum>25</RecNum><DisplayText>[14]</DisplayText><record><rec-number>25</rec-number><foreign-keys><keyapp="EN"db-id="rre2xxpar5fzvmef0w8vsw2o529tzzv2zt5t"timestamp="1521787743">25</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Spear,E.</author><author>Ng,D.T.</author></authors></contributors><auth-address>DepartmentofBiochemistryandMolecularBiology,ThePennsylvaniaStateUniversity,UniversityPark,PA16802,USA.</auth-address><titles><title>Theunfoldedproteinresponse:nolongerjustaspecialteamsplayer</title><secondary-title>Traffic</secondary-title><alt-title>Traffic(Copenhagen,Denmark)</alt-title></titles><periodical><full-title>Traffic</full-title><abbr-1>Traffic(Copenhagen,Denmark)</abbr-1></periodical><alt-periodical><full-title>Traffic</full-title><abbr-1>Traffic(Copenhagen,Denmark)</abbr-1></alt-periodical><pages>515-23</pages><volume>2</volume><number>8</number><edition>2001/08/08</edition><keywords><keyword>Animals</keyword><keyword>CellNucleus/*metabolism</keyword><keyword>EndoplasmicReticulum/*metabolism</keyword><keyword>FungalProteins/metabolism</keyword><keyword>Humans</keyword><keyword>Models,Biological</keyword><keyword>ProteinDenaturation</keyword><keyword>ProteinFolding</keyword><keyword>SignalTransduction</keyword><keyword>Stress,Physiological</keyword></keywords><dates><year>2001</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1398-9219(Print) 1398-9219</isbn><accession-num>11489209</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[14]。ATF6（激活轉錄因子6）是一種具有轉錄后調節(jié)活性的亮氨酸拉鏈DNA結合蛋白，本質上是一種以90kDA形式表達的膜蛋白，有一個大腔域和一個DNA結合結構域。UPR（unfoldedproteinresponse）途徑激活時，ATF6被剪切成其50kDa的分子，從胞漿轉位進入胞核，并激活與UPR相關的基因轉錄ADDINEN.CITE<EndNote><Cite><Author>Haze</Author><Year>1999</Year><RecNum>24</RecNum><DisplayText>[15]</DisplayText><record><rec-number>24</rec-number><foreign-keys><keyapp="EN"db-id="rre2xxpar5fzvmef0w8vsw2o529tzzv2zt5t"timestamp="1521772039">24</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>KyosukeHaze</author><author>HiderouYoshida</author><author>HidekiYanagi</author><author>TakashiYura</author><author>KazutoshiMori</author></authors></contributors><titles><title>MammalianTranscriptionFactorATF6IsSynthesizedasaTransmembraneProteinandActivatedbyProteolysisinResponsetoEndoplasmicReticulumStress</title><secondary-title>MolecularBiologyoftheCell</secondary-title></titles><periodical><full-title>MolecularBiologyoftheCell</full-title></periodical><pages><styleface="normal"font="default"size="100%">3787</style><styleface="normal"font="default"charset="134"size="100%">–3799</style></pages><volume>Vol.10</volume><dates><year>1999</year></dates><urls></urls></record></Cite></EndNote>[15]。ATF6是內質網應激反應順式元件的啟動子ADDINEN.CITE<EndNote><Cite><Author>Yoshida</Author><Year>1998</Year><RecNum>2</RecNum><DisplayText>[16]</DisplayText><record><rec-number>2</rec-number><foreign-keys><keyapp="EN"db-id="rre2xxpar5fzvmef0w8vsw2o529tzzv2zt5t"timestamp="1521602289">2</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>HiderouYoshida</author><author>KyosukeHaze</author><author>HidekiYanagi</author><author>TakashiYura</author><author>KazutoshiMori</author></authors></contributors><titles><title>Identificationofthecis-ActingEndoplasmicReticulumStressResponseElementResponsibleforTranscriptionalInductionofMammalianGlucose-regulatedProteins</title><secondary-title>THEJOURNALOFBIOLOGICALCHEMISTRY</secondary-title></titles><periodical><full-title>JBiolChem</full-title><abbr-1>TheJournalofbiologicalchemistry</abbr-1></periodical><pages><styleface="normal"font="default"size="100%">33741</style><styleface="normal"font="default"charset="134"size="100%">–33749</style></pages><volume>Vol.273,No.50</volume><number>December11</number><dates><year>1998</year></dates><urls></urls></record></Cite></EndNote>[16]，其作用是在內質網應激反應過程中引導分子伴侶轉錄ADDINEN.CITE<EndNote><Cite><Author>Roy</Author><Year>1999</Year><RecNum>7</RecNum><DisplayText>[17]</DisplayText><record><rec-number>7</rec-number><foreign-keys><keyapp="EN"db-id="rre2xxpar5fzvmef0w8vsw2o529tzzv2zt5t"timestamp="1521602310">7</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>BinayakRoy</author><author>AmyS.Lee</author></authors></contributors><titles><title>Themammalianendoplasmicreticulumstressresponseelementconsistsofanevolutionarilyconservedtripartitestructureandinteractswithanovelstress-induciblecomplex</title><secondary-title>OxfordUniversityPress</secondary-title></titles><periodical><full-title>OxfordUniversityPress</full-title></periodical><pages><styleface="normal"font="default"size="100%">1437</style><styleface="normal"font="default"charset="134"size="100%">–1443</style></pages><volume>27,No.6</volume><number>NucleicAcidsResearch</number><dates><year>1999</year></dates><urls></urls></record></Cite></EndNote>[17]。ATF6β（ActivatingTranscriptionFactor6Beta），早期稱為環(huán)磷酸腺苷反應元件結合蛋白相關蛋白（G13），是ATF6的一種異構形式ADDINEN.CITEADDINEN.CITE.DATA[18]。ATF6β能獨立激活UPR相關蛋白的表達ADDINEN.CITEADDINEN.CITE.DATA[19]。比如葡萄糖調節(jié)蛋白78（glucose-regulatedprotein78,GRP78），ATF6β是內質網應激中功能活性中非常重要的一部分ADDINEN.CITE<EndNote><Cite><Author>Thuerauf</Author><Year>2007</Year><RecNum>20</RecNum><DisplayText>[20]</DisplayText><record><rec-number>20</rec-number><foreign-keys><keyapp="EN"db-id="rre2xxpar5fzvmef0w8vsw2o529tzzv2zt5t"timestamp="1521686781">20</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Thuerauf,DonnaJ.</author><author>Marcinko,Marie</author><author>Belmont,PeterJ.</author><author>Glembotski,ChristopherC.</author></authors></contributors><titles><title>EffectsoftheIsoform-specificCharacteristicsofATF6αandATF6βonEndoplasmicReticulumStressResponseGeneExpressionandCellViability</title><secondary-title>JournalofBiologicalChemistry</secondary-title></titles><periodical><full-title>JournalofBiologicalChemistry</full-title></periodical><pages>22865-22878</pages><volume>282</volume><number>31</number><dates><year>2007</year></dates><isbn>0021-9258 1083-351X</isbn><urls></urls><electronic-resource-num>10.1074/jbc.M701213200</electronic-resource-num></record></Cite></EndNote>[20]。我們推測可能與ATF6β高表達不利于乳腺癌患者預后與該基因能獨立激活UPR相關蛋白的表達有關?；蚩截悢翟黾油ǔ鸹虮磉_上升ADDINEN.CITEADDINEN.CITE.DATA[21,22]，本文發(fā)現(xiàn)ATF6β表達水平與其基因拷貝變化正相關；異常的啟動子DNA過度甲基化通常是導致基因沉默的調節(jié)因素之一，有研究報道了DNA甲基化影響了乳腺癌的基因表達譜，從而影響了乳腺癌的分型，同時也被作為某些癌癥治療的靶點ADDINEN.CITEADDINEN.CITE.DATA[23]。在我們的研究中，ATF6β基因甲基化水平與其表達水平呈負相關，說明基因低甲基化促進了ATF6β表達。本文運用多組學高通量數據庫分析乳腺癌患者樣本，基于數據庫數據大，隨訪時間長，組學數據完備，ATF6β高表達不利于乳腺癌患者預后這一結果的可信度高，可作為乳腺癌預后的一個潛在標志物。但也存在一些不足，如分析結果受到樣本來源的限制。后續(xù)研究中，課題組會在更多臨床乳腺癌患者樣本中驗證ATF6β的表達差異，并進一步研究ATF6β參與乳腺癌進展的分子機制。

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