乳腺癌是女性常见的恶性肿瘤[1]，2015年我国新增乳腺癌病人约27×104人，死亡约7×104人[2]. 根据乳腺癌细胞所携带雌激素受体(estrogen receptor, ER)和人表皮生长因子受体(human epidermal growth factor receptor 2, HER2)等标志物的差异，乳腺癌可分成Luminal A (ER+, HER2-)、Luminal B(ER+, HER2+)、三阴性(ER-, HER2-)和HER2(ER-, HER2+)型，约74%的乳腺癌是ER+，其发病具有雌激素依赖性[3]. 目前发现，多种EDCs(environmental endocrine disrupting chemicals, 环境内分泌干扰物)由于具有雌激素活性，也能够促进乳腺细胞增殖，诱发乳腺癌的发生，如己烯雌酚(diethylstilbestrol, DES)，有机氯农药(DDT, DDE等)和多环芳烃(polycyclic aromatic hydrocarbon, PAHs)等[3-4]. 但是多数EDCs与雌激素核受体(nuclear estrogen receptor，nER)结合能力很低[5-6]，有学者[7]认为，环境本底剂量的EDCs并不足以诱发人体乳腺癌的发生. 另外，EDCs诱导乳腺细胞增殖作用机制的研究主要集中在基因组、非基因组信号通路激活或改变细胞周期等方面，而对各通路间的交互作用研究较少. 因此，该研究在归纳整理国内外相关研究基础上，总结分析了EDCs对乳腺癌细胞的增殖作用，并对其分子机制进行了全面综述，同时展望了未来研究的方向，以期为乳腺细胞增殖机制的深入研究提供参考.

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1 具有雌激素活性的EDCs对乳腺细胞的增殖作用

1.1 雌激素在乳腺癌发生中起关键作用

雌激素可促进乳腺细胞有丝分裂和细胞增殖，增加DNA损伤的可能性、改变DNA甲基化水平等，从而提高乳腺癌发病风险[3,8]，目前研究[3]已经证实，ER+Luminal乳腺癌危险因素与雌激素直接相关. 大鼠试验也证明，在缺乏雌激素的情况下，即使采用乳腺致癌物二甲基苯并蒽〔7,12-dimethylbenz(a)anthracene, DMBA〕暴露也不产生乳腺肿瘤[9]，表明雌激素在乳腺癌发生中起关键作用.

1.2 具有雌激素活性的EDCs可促进乳腺细胞的增殖

由表1可见，天然、人工合成激素、农药、酚类等EDCs均对乳腺细胞具有增殖作用，主要是因为这些物质具有雌激素活性，能通过结合nER或膜雌激素受体(membrane estrogen receptor, mER)等，激活基因组、非基因组信号通路，进而调控细胞周期、抑制细胞凋亡和促进乳腺细胞增殖. 一般来说，具有较强雌激素活性的EDCs对乳腺细胞的增殖作用较强；较弱雌激素活性的促细胞增殖能力较弱，但有研究表明,长时间、高剂量暴露也可增加乳腺肿瘤发病的风险[10]，不管雌激素活性的高低，EDCs和致癌物联合暴露，都会增加患乳腺癌的风险，如双酚A(BPA)与DMBA联合暴露大鼠，发生乳腺肿瘤的潜伏期比DMBA单独暴露显著缩短，对切除卵巢的裸鼠补充E2或BPA后，均可形成乳腺肿瘤[11].

 

表1 不同EDCs对乳腺细胞的增殖效应Table 1 Proliferative effects of different EDCs on breast cells

  

EDCs分类物质名称途径生物学效应风险数据来源天然雌激素雌二醇ERα，GPR30∕ERK，Bcl⁃2细胞增殖，抑制凋亡，细胞周期加快确定文献[6，12⁃13]合成雌激素炔雌醇，己烯雌酚ERα细胞增殖确定文献[6]烷基酚，三氯生ERα，cyclinD1细胞增殖，细胞周期加快潜在文献[6，14⁃15]酚类二苯酮，壬基酚ERα，cyclinD1细胞增殖和转移，细胞周期加快潜在文献[6，16]双酚AERα，ERR，GPR30，cyclinD1细胞增殖，抑制细胞凋亡，细胞周期加快确定文献[12，17⁃21]双酚SERα，GPR30∕ERK细胞增殖潜在文献[17，22]DDT，DDEERα，GPR30细胞增殖确定文献[12，23]农药阿特拉津ERα，GPR30∕ERK细胞增殖和迁移，细胞周期加快确定文献[24]十氯酮，甲氧滴滴涕ERα细胞增殖潜在文献[25]多溴联苯醚ERα，ERK；PKC细胞增殖，抑制细胞凋亡，细胞周期加快潜在文献[26]阻燃剂TCP，TPP，TDCPPERα细胞增殖潜在文献[27]TBBPA，HBCDERα细胞增殖潜在文献[28]持久性有机污染物多氯联苯ERα细胞增殖确定文献[29]二英AhR∕CYP1A1信号通路交互，细胞增殖，抑制细胞凋亡确定文献[30⁃31]植物雌激素大豆异黄酮ERα细胞增殖无风险文献[32]毛蕊异黄酮GPR30抑制细胞增殖无风险文献[33]邻苯二甲酸酯类邻苯二甲酸酯AhR，ERα，PI3K∕Akt，Bcl⁃2细胞增殖，抑制细胞凋亡潜在文献[13，34]对羟基苯甲酸酯类对羟基苯甲酸酯ERα，GPR30∕ERK，cyclinD1细胞增殖，抑制细胞凋亡，细胞周期加快潜在文献[35⁃38]重金属Cd非ERα依赖，EGFR细胞增殖，恶性转化确定文献[39]

注： TCP—磷酸三甲苯酯; TPP—磷酸三苯基酯; TDCPP—磷酸三(1,3-二氯-2-丙基)酯; TBBPA—四溴双酚A; HBCD—六溴环十二烷.

  

图1 EDCs促进乳腺细胞增殖的分子机制Fig.1 Molecular mechanisms through which EDCs promote proliferation of breast cells

1.3 EDCs与乳腺癌的发生有较高的相关性

EDCs不仅能促进乳腺细胞增殖，而且流行病学研究表明，EDCs暴露与乳腺癌的发生直接相关，如多氯联苯与因纽特妇女乳腺癌风险显著正相关[40]；居住在含有机氯农药垃圾附近的妇女相比生活在远离该处的妇女患乳腺癌的几率高3倍[41]. 乳腺不同发育阶段对EDCs的敏感性也不同，初潮和第一次妊娠期是乳腺癌发生的关键窗口期[42]，如Cohn等[43]研究发现，受DDT暴露的青春期女孩成年后乳腺癌发病升高；妊娠期使用DES的妇女患乳腺癌的风险增加[44]，其女儿患乳腺癌的风险也有增加[45]；值得注意的是，大豆异黄酮等植物雌激素虽能促进乳腺细胞的增殖[32]，但是流行病学研究结果[46]表明,它并不是乳腺癌发生的危险因子.

2 EDCs促进乳腺细胞增殖的分子机制

2.1 EDCs通过与雌激素受体结合，促进乳腺细胞的增殖

2.1.1 EDCs通过结合核受体，促进乳腺细胞的增殖

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事实上，η值平方可积函数空间L2(Γ;η)是η与L2(Γ)的张量积空间,即L2(Γ;η)≅L2(Γ)⊗η。

经典的研究[47]认为，E2能够调控乳腺细胞周期和增殖主要是E2与ERs(ERα、ERβ)结合后，增强或抑制靶启动子区ERE的转录，促进或抑制相关基因和蛋白表达完成的(见图1). 目前诸多研究[6,48]表明，人工合成雌激素、烷基酚、有机氯杀虫剂、苯甲酸酯等100多种化合物具有类似E2的酚羟基结构，能与ER结合，从而激活增殖相关基因的表达，促进细胞增殖. 有机氯农药DDT、DDE[23]，十氯酮(chlordecone)、甲氧滴滴涕(methoxychlor)[25]，对羟基苯甲酸甲酯(methylparaben, mePB)[35]以及BPA同系物BPS、BPAF等[17,21]均通过与ER结合，促进乳腺癌细胞MCF-7的增殖，增殖程度主要取决于其与ER结合能力，即EDCs三维空间结构、极性、疏水性以及与ERα活性口袋中氨基酸残基形成H键的能力等[17,49]，如双酚类化合物(BPs)与ERα的亲和即依赖于H键与His524[49].

EDCs与ER结合后形成二聚化的ER入核，也可不直接与ERE结合，而与转录因子AP1(activator protein)、SP1(stimulator protein)或NF-κB(nuclear factor-kappa B)等相互作用，激活非ERE依赖的基因组模式，进而调节靶基因转录(见图1). WU等[50]报道，在转染了ERαSp13荧光素酶报告基因质粒的MCF-7细胞中，壬基酚(NP)、BPA、开蓬(kepone)、辛基酚(OP)等均可选择性地激活不同类型的Sp，产生强度各异的雌激素活性；在转染ERα、ERβ和共激活因子SRC-1(steroid receptor activator 1)、转录中间因子TIF2(transcriptional intermediary factor 2)的Hela细胞中，染料木黄酮(genistein, Gen)、BPA和OP等都具有募集SRC-1、TIF2的能力，有助于外源雌激素发挥其激动或拮抗效应[51]；而且，BPA还能上调ER+乳腺癌细胞中SRC-1和SRC-3的蛋白质水平和促进ERE活性[52]. 这些研究表明，BPA和OP等与ERα结合能力并不强的EDCs[6,17]，却有较强促乳腺细胞增殖的能力，可能与它们结合ER后又促进转录因子的招募有关.

除了nER外，EDCs还可与雌激素相关受体(estrogen related receptors, ERRs)和芳香烃受体(aryl hydrocarbon receptor, AhR)两种核受体结合，进而促进细胞增殖. ERRs与ER具有很高的相似性和同源性，但无天然配体，属于孤儿核受体家族，有ERRα、ERRβ和ERRγ 3个紧密相关的成员，其中ERRα和ERRγ与乳腺癌的不良预后有关[53]. 外源ERRγ转染MCF-7后，细胞增殖加快，而且ERRγ还可增强ERE的转录[54]. 体外[3H]标记竞争结合试验表明，BPA与ERRγ的亲和力很强(KD, 5.5～5.7 nmolL)[55]，10 nmolL BPA能以时间依赖性的方式上调MCF-7和SkBr3中ERRγ的mRNA和蛋白水平，并诱发ERRγ核内定位，结合雌激素相关受体反应元件(ERRE)序列，促进细胞的增殖[18]，以及促进三阴性乳腺癌细胞的迁移[56].

某些EDCs能够引起AhR应答，促进细胞增殖，而目前并没有发现强亲和性的内源AhR配体，这些EDCs更值得关注. 如Hsieh等[34]研究表明，邻苯二甲酸酯(phthalates)通过与AhR结合，激活cAMP-PKA-CREB1信号通路，上调组蛋白脱乙酰基酶(HDAC6)和原癌基因c-Myc的表达，进而促进MDA-MB-231(ER-)的增殖. 四氯二苯并-p-二英(TCDD) 通过AhR，诱导乳腺癌细胞增殖和抑制细胞凋亡[31]，激活β-连环蛋白(β-catenin)和PI3KAkt通路，显著增加乳腺细胞微球体的数目和体积[30].

2.1.2 EDCs通过结合膜受体，促进乳腺细胞的增殖

E2或EDCs促细胞增殖的另一重要途径是激活非基因组信号通路，通过与GPR30(G protein-coupled estrogen receptor, GPER或GPR30)等膜受体结合，激活胞外信号调节激酶(extracellular signal-regulated kinases，ERK)，改变靶蛋白活性或靶基因表达，促进细胞增殖[57]. 体外[3H]E2受体结合试验[12]表明，Gen、BPA、NP、Kepone、p,p′-DDT、o,p′-DDE等EDCs对GPR30均具有不同程度的结合能力，相对结合力最高为E2的13.41%. EDCs可能是通过结合GPR30、ERα36、HER以及其他mERs激活快速非基因组信号通路，从而加速乳腺细胞的增殖(见图1). 如BPA与ERα的结合力比E2低 10 000 倍[5]，但与GPR30的结合力为E2的2.83%，且能大幅提高第二信使cAMP的浓度[12]，激活相关靶蛋白，说明BPA可能主要是通过GPR30产生增殖效应.

选取2016年7月至2017年6月期间,我院收治的40例凶险型前置胎盘患者作为观察组,选取同时期80例普通型前置胎盘患者作为对照组。所有患者均通过产前超声检查以及产后胎盘检查确诊为前置胎盘;其中前置胎盘诊断标准为:妊娠28周以上,胎盘处于子宫下段部位,下缘达到甚至覆盖宫颈内口;通过既往剖宫产史以及患者妊娠晚期影像诊断确诊胸线下前置胎盘。

EDCs还可与mERα和mERβ结合，从而促进细胞增殖. mERα和mERβ是ERα和ERβ经过十六烷酰化后，定位在细胞膜上小窝部位而形成的膜受体[58]. 体外报告基因试验证明，BPS与nER的结合能力并不强，仅约为BPA的0.6倍[5]，但Vinas等[22]研究表明，纳摩尔级BPS可通过与大鼠垂体瘤GH3B6F10细胞mERα结合，激活促细胞增殖的ERK信号通路，且不激活主导凋亡的JNK通路，从而对细胞增殖的效应达到甚至超过E2水平. 因此，在评价EDCs的乳腺细胞的增殖作用时，mER介导的非基因组信号通路不可忽视.

2.2 EDCs通过改变乳腺细胞周期，促进乳腺细胞的增殖

细胞增殖过程也称为细胞周期，长短主要取决于G1期，其受细胞周期蛋白(cyclin)、周期依赖性蛋白激酶(cyclin-dependent kinases，CDKs)、细胞周期抑制因子(cyclin-dependent kinases inhibitor，CKI)等调控. CDKs属于丝苏氨酸激酶家族，在细胞周期中的水平相对稳定，其活性受cyclin D等细胞周期蛋白水平的调控. 研究[15,19]表明，EDCs通过上调cyclin D及下调CKI，改变乳腺细胞周期，促进乳腺细胞的增殖(见图1). cyclin D和c-Myc蛋白过表达在乳腺癌中较为常见[59]，cyclin D1启动子虽然无ERE序列区，但在-143～-110区有3个富含GC的Sp1结合位点，可以ERαSp1方式对E2产生响应[60]，而且cyclin D1能增强ER与ERE的结合能力，上调雌激素介导的转录[61]，调控细胞增殖. EDCs引起乳腺癌细胞增殖的另一个靶点是c-Myc[62]. Wrobel等[36]研究发现，对羟基苯甲酸酯通过影响MCF-10A细胞中细胞周期相关基因表达，加速细胞从G1期向S期的转变，从而促进细胞增殖. WU等[19]研究发现，BPA上调乳腺细胞HBL-100中cyclin D1和CDK4，促进细胞进入G2M 期，促进乳腺细胞增殖. Dairkee等[63]研究表明，BPA通过下调细胞周期抑制因子p53、p21和Bax，同时上调增殖细胞核抗原PCNA、CDKs和pRb等促增殖相关蛋白，从而促进乳腺癌细胞T47D的增殖.

2.3 EDCs通过抑制细胞凋亡，促进乳腺细胞的增殖

研究[64]表明，E2还可通过上调凋亡抑制蛋白Bcl-2和Bcl-xL的表达，进而促进乳腺癌细胞增殖. 细胞凋亡的内源途径中，凋亡因子Cyt c的释放是关键，源于线粒体外膜通透性的改变，其通透性主要受到Bcl-2(B cell lymphoma gene 2)抗凋亡基因家族的调控[65]，BCL-2家族可分为两大类： 抑制凋亡的Bcl-2 亚家族(包括Bcl-2、Bcl-xL等)和促进凋亡的Bax亚家族(包括Bax、Bak等). EDCs也可通过抑制乳腺细胞的凋亡，导致乳腺细胞的数目增多，从而促进细胞增殖(见图1). 纳摩尔级邻苯二甲酸酯可显著上调Bcl-2蛋白的表达[13]，而且还可通过上调Bcl-2Bax的比值，而抑制了他莫昔芬(tamoxifen)对MCF-7的凋亡作用[66]. 纳摩尔级BPA可激活EGFRERK信号通路，上调Bcl-2蛋白表达，促进细胞增殖[20]，且能增强ER+和ER-乳腺癌细胞对阿霉素(doxorubicin)等多种抗癌药物的耐药性[67].

2.4 EDCs通过多条信号途径的交互，促进乳腺细胞的增殖

研究表明，E2或EDCs介导基因组信号和非基因组通路在核内存在交汇，调控细胞增殖，如纳摩尔级BPA即可通过结合GPER，激活ERK信号通路，上调转录因子AP1中的c-fos，进而上调雌激素调节蛋白pS2 mRNA的表达[68]和促进细胞增殖[69]. 4,4′-二羟基二苯硫醚(4,4′-thiodiphenol, TDP)，作为BPA的一种衍生物，通过GPR30激活PI3KAkt和ERK通路，且与ERα通路交互，共同促进MCF-7的增殖[70]. ER+乳腺癌细胞膜受体HER2被其配体HRG(recombinant human heregulin-β1)激活后，通过激活PI3KAkt信号通路，引起ERα的Ser167磷酸化，显著降低了促进其细胞增殖所需对羟基苯甲酸酯的剂量[71]. 另外，ERα上还有多个磷酸化位点，可被ERK12[72]、PI3KAkt[73]和PKA[74]等激活，而ERα的磷酸化激活在基因转录中起关键作用，如增强配体与ER结合、核内定位、二聚化、DNA结合、激活因子的招募等[75]，这就使mER介导的快速、非基因组效应与nER介导的基因组效应产生交互作用(cross-talk). 但高剂量G1(GPER激活剂)却能通过抑制E2和外源性雌激素诱导的转录激活以及调节细胞周期蛋白的信号级联，而抑制MCF-7增殖[76]，表明这种交互作用是复杂的.

而cyclin D和c-Myc是雌激素信号通路和细胞周期调控因子在细胞核内的交汇点，也就是雌激素结合mER，激活ERK、PI3K等信号通路，进而磷酸化核内ERα二聚体，上调c-Myc和cyclin D1，再通过CDK磷酸化Rb，释放转录因子E2F1，进而加速细胞从G1期向S期的转变[77-79]. LI等[26]研究发现，PBDE-209可激活MCF-7和耐药株MCF-7ADR细胞中的蛋白激酶C(PKCα)和ERK12，抑制细胞凋亡，增加S或G2M期细胞比例，从而促进细胞增殖. 三氯生(TCS)、OP、二苯酮(BP1)和NP均可上调MCF-7中cyclin D1 mRNA和蛋白的表达水平，下调p21 mRNA表达，ER拮抗剂ICI 182780可阻断其效应，表明TCS、OP、BP1和NP对细胞周期的改变是通过ER途径介导的[15-16]. 而且，ERα还可被CDK2cyclin A[80]和CDK7[81]等周期蛋白激酶磷酸化激活，产生交互作用. 由此可见，EDCs对乳腺细胞的增殖效应，往往是基因组和非基因组信号通路的激活、抑制细胞凋亡以及改变细胞周期的综合效应.

3 展望

3.1 从与内源激素交互的角度探讨EDCs对乳腺细胞的增殖机制

目前探讨EDCs对乳腺细胞的增殖作用，均使用无酚红培养基添加碳吸附胎牛血清进行，这虽可排除培养基中小分子激素的干扰，但这也忽略了乳腺组织细胞中一些内源激素的存在以及与EDCs产生的交互作用，而低估了EDCs的增殖效应. 研究表明，大约10%的乳腺癌是Luminal B (ER+, HER2+)型[3]，其增殖依赖于ER和HER，且有研究发现，超过48%的乳腺肿瘤表达HER配体[82-83]，乳腺细胞因此可能通过自身产生HER配体而增强其对EDCs的反应. 如对羟基苯甲酸丁酯(BP)与ERα结合能力比E2低 10 000 倍[84]；MCF-7增殖试验中，激活ERα所需要BP的剂量也是难以置信的高[85]；然而，乳腺癌细胞BT-474(ER+, HER2+)中HER2被其配体HRG激活后，通过PI3KAkt通路磷酸化ERα的Ser167，促进p-ERα在c-Myc增强子上的募集，促进细胞增殖所需BP的剂量显著降低[70]. 因此，有必要在HER配体存在的情况下，重新评估某些EDCs对乳腺细胞的增殖能力.

3.2 从影响E2合成角度探讨EDCs对乳腺细胞的增殖机制

[12] THOMAS P,DONG Jing.Binding and activation of the seven-transmembrane estrogen receptor GPR30 by environmental estrogens:a potential novel mechanism of endocrine disruption[J].Journal of Steroid Biochemistry and Molecular Biology,2006,102:175-179.

绝经后妇女体内雌激素主要由肾上腺、脂肪和乳腺等组织产生，E2合成有芳香化酶和硫酸酯酶两条途径，芳香化酶(CYP19A)和硫酸转移酶(SULT1E1)分别是两条途径的关键酶[88]. Wrobel等[38]研究发现，在乳腺癌细胞MCF-7细胞中，对羟基苯甲酸酯通过上调CYP19A基因及蛋白表达，增加E2内源合成，促进细胞增殖. 因此，在探讨EDCs对乳腺细胞的增殖机制时，需要考虑其对激素合成和代谢的影响，以免低估了EDCs促乳腺细胞增殖能力.

3.3 从低剂量联合作用角度探讨EDCs对乳腺细胞的增殖作用

环境及人体中的EDCs是低剂量且多种同时存在，混合物中各组分可以在其不同的靶位点通过不同的作用方式产生增殖效应，且不同的作用靶点和作用方式之间还存在着交互影响，使细胞增殖途径更为复杂、交错. 有研究[89]表明，BPA与含有植物雌激素的豆奶粉提取物联合暴露MCF-7存在加和现象；而E2、炔雌醇(EE2)、BPA、NP、OP、Gen的联合暴露增殖效应低于加和现象，是由于NP、OP与其他EDCs有拮抗效应[90]；但Silva等[91]研究表明，将8种各自浓度均低于无观察效应浓度(NOECs)的弱雌激素混合在一起，却能够显著促进MCF-7细胞增殖，即所谓的“无中生有”(something from nothing)，这表明只专注单一化合物的效应，可能会低估EDCs促乳腺细胞增殖的能力.

[8] BOYNE D J,FRIEDENREICH C M,MCINTYRE J B,et al.Endogenous sex hormone exposure and repetitive element DNA methylation in healthy postmenopausal women[J].Cancer Causes & Control,2017,28(12):1369-1379.

4 结论

a) 环境因子可能在乳腺癌发病中发挥了关键作用，其中EDCs通过所具有雌激素活性，促进乳腺细胞的增殖，进而有助于乳腺癌的发生和加快癌症进程.

b) 目前已知EDCs促进乳腺细胞增殖的分子机制包括激活雌激素受体信号通路、抑制细胞凋亡、改变细胞周期等，且各通路之间存在复杂的交互作用，这些综合效应促进了乳腺细胞的增殖.

在这个年龄段是即将退休或已退休，可选购的产品较少，可首选意外险，在符合条件的情况下选择健康险。随着保险产品的优化，有许多保险公司推出老年人意外险及老年人防癌险，这两款产品的性价比都是较高的，可以尽早入手。

c) 目前的研究可能低估了EDCs的增殖效应，今后应从与内源激素交互、影响雌激素合成以及低剂量联合作用等方面来全面评价EDCs产生的增殖效应和探讨其作用机制.

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微网站和微信公众平台之间有一定的独立性，但并不是完全隔离。微网站的主要栏目和页面都开发出来以后，需要与微信公众平台做进一步的链接和功能整合。在微信公众平台中设置关键字回复，可以链接至微网站首页或某个栏目；微信公众平台的主菜单可以添加链接，跳转至微网站或微网站的某个栏目；微信公众平台原本发布的图文消息，也可以被微网站调用。丰富多样具有交互性的调用形式使这种模式构建的学习平台更加灵活、便捷、高效。

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当油箱增加的长度ΔL设为0.1 m、0.2 m时，油箱的体积对应增加了100 L、200 L。系统最终达到平衡后的油箱温度分别为97.3 ℃，94.7 ℃，如图8所示。由此可得增加油箱体积的散热效果比增加肋板更有效，但是只增加油箱体积也无法将油液温度降低到80 ℃。

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翠姨越来越瘦了，哥哥去到外祖母家看了她两次，也不过是吃饭，喝酒，应酬了一番。而且说是去看外祖母的。在这里年青的男子，去拜访年青的女子，是不可以的。哥哥回来也并不带回什么欢喜或是什么新的忧郁，还是一样和大家打牌下棋。

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