摘要
[背景和目的]
乳腺癌是全世界妇女中最常见的恶性肿瘤之一。在多数国家,乳腺癌的发病率和死亡率呈上升趋势,每年全世界大约有130万人被诊断为乳腺癌,占全部女性恶性肿瘤总数21%,而有约40万人死于该病。它严重威胁着妇女的生命和健康。针对乳腺癌的预防、诊断和治疗,虽然在诊断技术、化疗、手术、放疗、内分泌治疗及生物治疗方面取得了鼓舞人心的成果,然而,目前的预防、诊断和治疗手段仍然十分有限,这为乳腺癌的深入研究留下了极大的探索空间。
随着分子生物学技术的发展,人们发现组蛋白去乙酰化调控作为一种重要的表观遗传修饰,通过调节组蛋白乙酰化酶(Histone acetylase,HAT)和组蛋白去乙酰化酶(Histone deacetylase,HDAC)之间的这种动态平衡,参与了许多恶性肿瘤(包括成神经细胞瘤、黑色素瘤、白血病、前列腺癌、肺癌、卵巢癌和结肠癌等)的发生发展。
对于乳腺癌而言,有学者从雌激素受体(ER)信号通路、BRCA1基因、HER-2基因、细胞分化、细胞凋亡、干细胞等领域进行研究,证实组蛋白去乙酰化调控与乳腺癌也是密切相关的。我们将构建组蛋白去乙酰化酶1(HDAC1)质粒,筛选高效的组蛋白去乙酰化酶抑制剂,以此对组蛋白去乙酰化调控进行双向干预,对比观察乳腺癌雌激素受体状况不同的细胞株增殖行进的改变,观察它对周期素CyclinD1、CyclinA2的影响,从细胞增殖这一最基本的生命活动的角度来探讨组蛋白去乙酰化调控乳腺癌细胞的机制,进而通过动物模型评价组蛋白去乙酰化酶抑制剂单用以及与化疗药物联合使用的疗效和副作用。通过此研究,可望在技术上建立转染组蛋白去乙酰化酶1(HDAC1)的乳腺癌细胞模型和乳腺癌动物模型,为相关研究提供实验模型;在理论上通过研究组蛋白去乙酰化调控与细胞周期密切相关的周期素CyclinD1、CyclinA2的表达,从周期素的角度探讨组蛋白去乙酰化调控对乳腺癌作用的机制。重要的是在临床实践方面,探索组蛋白去乙酰化酶抑制剂对乳腺癌细胞增殖影响的时效及量效关系,借助动物模型研究其对乳腺癌的疗效及副作用,为寻求乳腺癌的治疗新途径提供一定的实验依据,为乳腺癌的以组蛋白去乙酰化酶为靶标的抗癌药物研发提供有益义的实验参考。
[方法]本研究包括四部分
1、组蛋白去乙酰化酶1对乳腺癌细胞增殖周期的影响(正向干预)
1.1通过基因亚克隆(Subcloning)技术构建带有HA标签的组蛋白去乙酰化酶1质粒(pcDNA3.1-HA-hdac1);
1.2 CaCl_2法制备感受态细菌(E.coli);
1.3 pcDNA3.1-HA-hdac1质粒转化感受态细菌(E.coli)扩增质粒,进行质粒提纯、酶切鉴定及DNA测序;
1.4 pcDNA3.1-HA-hdac1质粒分别转染雌激素受体阳性及阴性两种细胞株,用Western印迹法检测质粒蛋白表达;
1.5流式细胞术检测转染质粒后细胞周期的变化。
2、组蛋白去乙酰化酶抑制剂对乳腺癌细胞增殖的影响(负向干预)
2.1 MTT比色法观察TSA、SAHA、CS055、MS-275四种组蛋白乙酰化酶抑制剂对雌激素受体状况不同的乳腺癌细胞增殖的影响;(筛选抑制剂)
2.2流式细胞术检测不同浓度的组蛋白乙酰化酶抑制剂作用后细胞周期变化。(确定抑制剂浓度)
3、组蛋白去乙酰化双向调控对乳腺癌相关基因表达影响的研究
3.1 pcDNA3.1-HA-hdac1质粒转染乳腺癌细胞(正向干预);
3.2组蛋白去乙酰化酶抑制剂处理乳腺癌细胞(负向干预);
3.3 Western印迹法检测周期素Cyclin D1,Cyclin A2蛋白的表达;
3.4流式细胞术检测细胞表达周期素Cyclin D1,CyclinA2的细胞。
4、组蛋白去乙酰化酶抑制剂对乳腺癌细胞增殖影响的动物实验研究
4.1饲养Balb/c-nu/nu(Crl:NU-Foxnlnu)雌性裸鼠(SPF级),细胞悬液皮下注射法构建人乳腺癌细胞裸鼠移植瘤模型;
4.2以上述体外实验所选定的组蛋白去乙酰化酶抑制剂的剂量为基线,再次设置剂量梯度,经尾静脉注射给药,筛选该抑制剂在动物体内的最佳有效剂量以开展下一步实验;
4.3荷瘤裸鼠随机分为6组(对照组、抑制剂组、紫杉醇组、阿霉素组、紫杉醇+抑制剂组、阿霉素+抑制剂组),分别给予相应的因素处理。1周后自尾静脉采血进行血细胞分析,并检测血脂、肝功能、肾功能主要指标,4周后称裸鼠体量,拉颈处死裸鼠,手术剥取肿瘤组织,称量瘤体湿重。计算肿瘤生长抑制率:(1-不同处理组瘤重/对照组瘤重)×100%。游标卡尺测量肿瘤最大长径(a)、横径(b),计算移植瘤的体积=(a×b~2)/2。
[结果]
1、组蛋白去乙酰化酶1对乳腺癌细胞增殖周期的影响(正向干预)
1.1组蛋白去乙酰化酶1质粒(pcDNA3.1-HA-hdac1)构建及鉴定:亚克隆构建组蛋白去乙酰化酶1质粒(pcDNA3.1-HA-hdac1)成功后,进行质粒提纯、酶切鉴定及DNA测序,证实hdac1 DNA片段为1449bp(克隆位点为BamHI/EcoR I);分别转染雌激素受体阳性及阴性两种细胞株,Western印迹法检出有HDAC1蛋白表达。
1.2组蛋白去乙酰化酶1对乳腺癌细胞增殖周期的影响转染HDAC1质粒后流式细胞术检测显示:雌激素受体阳性乳腺癌细胞株MCF-7的G0/G1期细胞比例下降(40.31±2.15)%,而S期细胞比例增加(17.98±1.87)%,P<0.05;雌激素受体阴性乳腺癌细胞株MDA-MB-435s的G0/G1期细胞比例下降(41.22±2.27)%,而S期细胞比例增加(16.70±2.33)%,P<0.05。两种细胞之间相比,P>0.05。
2、组蛋白去乙酰化酶抑制剂对乳腺癌细胞增殖周期的影响(负向干预)
2.1筛选抑制剂:TSA、SAHA、CS055和MS-275四种不同类型的组蛋白去乙酰化酶抑制剂处理细胞,均在细胞培养24h后就显示出对乳腺癌细胞生长的抑制作用,到了48h达到最大程度的抑制;在四种抑制剂中,SAHA显示出较强的抑制能力(在48h时间点上,SAHA组分别与TSA、CS055、MS-275组比较,P<0.05),对于MCF-7细胞株,SAHA在48h的细胞生长抑制率为(70.31±2.35)%;对于MDA-MB-435s细胞株48h的细胞生长抑制率为(78.36±2.01)%。两种细胞之间相比,差异无统计学意义,P>0.05。
2.2抑制剂浓度选择:用1.0、2.0、4.0、8.0、16.0μmol/L浓度梯度的SAHA处理细胞48h后,浓度为4.0μmol/L时S期细胞比例下降最明显(P<0.05),当浓度进一步增加,S期细胞比例未继续下降。
3、组蛋白去乙酰化双向调控对乳腺癌相关基因表达影响的研究
3.1转染HDAC1质粒(正向干预):对于CyclinA2,乳腺癌细胞株MCF-7表达周期素Cyclin A2蛋白的细胞数较对照组变化不明显,乳腺癌细胞株MDA-MB-435S中,表达周期素Cyclin A2蛋白的细胞数较对照组增加,增幅约8%;对于cyclinD1,乳腺癌细胞株MCF-7和MDA-MB-435S中表达周期素CyclinD1蛋白的细胞数较对照组减少,减幅约10%。
3.2用组蛋白去乙酰化酶抑制剂SAHA处理细胞(负向干预):乳腺癌细胞株MCF-7和MDA-MB-435S中,表达周期素Cyclin A2蛋白的细胞数较对照组均显著减少,而表达周期素Cyclin D1蛋白的细胞数较对照组明显增加。并且,在两种细胞株中,二者的增减幅度都超过40%。
4、组蛋白去乙酰化酶抑制剂对乳腺癌细胞增殖影响的动物实验研究
4.1动物体内筛选SAHA适宜的剂量:组蛋白去乙酰化酶抑制剂SAHA不同剂量作用于乳腺癌荷瘤裸鼠后,通过比较肿瘤体积及抑瘤率均显示出疗效,在0.10mg/kg～0.42 mg/kg剂量范围内,SAHA的治疗效应呈现剂量依赖关系,当剂量从0.42 mg/kg翻倍升高至0.84 mg/kg时,未再见到治疗效应的提升。
4.2治疗因素处理荷瘤裸鼠:对照组、SAHA组、紫杉醇组、阿霉素组、紫杉醇加SAHA组、阿霉素加SAHA组六组相比。
4.2.1疗效:肿瘤体积及抑瘤率:与对照组比均为P<0.05,差异有统计学意义,治疗组间两两相比,紫杉醇加SAHA组为优;
4.2.2副作用:①体重:含有紫杉醇或者阿霉素的组,体重下降;②血细胞分析:含有紫杉醇或者阿霉素的组,白细胞计数下降,在单一的紫杉醇(或者阿霉素)组与紫杉醇(或者阿霉素)联合SAHA组的比较中,白细胞计数未显示出下降的差异;③胆固醇、尿素氮和肌酐:与对照组比均为P>0.05;④血清谷丙转氨酶:与对照组比,其水平均有显著升高,P<0.05,在单一的紫杉醇组与紫杉醇联合SAHA组的比较中,显示出差异有统计学意义,P值小于0.05;⑤血清胆红素:与对照组比,含有紫杉醇或者阿霉素的组,其水平均有显著升高,P<0.05,在单一的紫杉醇(或者阿霉素)组与紫杉醇(或者阿霉素)联合SAHA的比较中,未显示出差异。
[结论]
1、组蛋白去乙酰化酶1(HDAC1)基因在雌激素受体阳性与阴性的乳腺癌细胞中均有表达,其表达对乳腺癌细胞增殖有促进作用;
2、在体外实验中,TSA、SAHA、CS055和MS-275四种不同类型的组蛋白去乙酰化酶抑制剂对乳腺癌细胞增殖均有抑制作用,其中SAHA对乳腺癌细胞增殖的抑制作用最强,它的抑制效应在48h时最明显,适宜浓度为4.0μmol/L;
3、组蛋白去乙酰化酶抑制剂SAHA能有效地通过调控Cyclin A2和Cyclin D1的表达,减少进入S期和M期细胞的比例,抑制细胞DNA的复制合成和细胞有丝分裂,使细胞更多地滞留于G1期,最终走向死亡,达到抑制乳腺癌细胞增殖的效果;
4、组蛋白去乙酰化调控乳腺癌细胞增殖受激素受体状况影响的差异无统计学意义;
5、在乳腺癌裸鼠动物模型实验中,组蛋白去乙酰化酶抑制剂SAHA有抑瘤效应,并且在0.10 mg/kg-0.42 mg/kg剂量范围内,呈现剂量依赖关系,0.42 mg/kg时的效应最明显,高于体外实验所需剂量;
6、组蛋白去乙酰化酶抑制剂SAHA单一用药的抑瘤效应低于传统的化疗药物紫杉醇或者阿霉素,但SAHA与紫杉醇或者阿霉素联合使用有协同增效作用;
7、组蛋白去乙酰化酶抑制剂SAHA作用于乳腺癌的荷瘤裸鼠后对肾功能(尿素氮、肌酐)及血清胆固醇、血细胞的毒副作用较小。对血清谷丙转氨酶有一定影响,但这种影响的程度并没有在联合了化疗药物的情况下而加重;
8、组蛋白去乙酰化酶抑制剂SAHA联合紫杉醇或者阿霉素有望成为乳腺癌的治疗新途径。
[Background and Objective]
Breast cancer is one of most common malignant tumors for woman in the world.In most countries,the incidence and the mortality rate of breast cancer is rising,there was about 1,300,000 people being diagnosed of breast cancer each year in the whole world, Accounting for 21%of the complete female malignant tumor total,and there was about 400,000 people died of breast cancer each year.So we can say that breast cancer is threatening woman's life and the health seriously.In view of breast cancer prevention, diagnosis and treatment,although the diagnosis technology,the chemotherapy,the surgery,the radiotherapy,the endocrine treatment and the biological treatment has yielded encouraging result,the current method of prevention,diagnosis and treatment were still limited,this was still enormous exploration space for the breast cancer research.
With the development of molecular biology,researchers found that histone deacetylation regulation is a kind of epigene modification for cells,it invoves in the occurrence and development of many malignant tumors(including neurocytoma, melanoma,leukemia,prostate cancer,lung cancer,ovarian cancer and colon cancer and so on) by adjusting the balance of histone acetylase(HAT) and histone deacetylase(HDAC).
As to breast cancer,some researchers studied in the field of the estrogen receptor (ER) signaling passway,the BRCA1 gene,the HER-2 gene,the cell differentiation,the cell apoptosis and stem cell and so on,they confirmed that histone deacetylation regulation is also involving in breast cancer.In this research,we will construct histone deacetylase 1(HDAC1) plasimid,screen the highly effective histone deacetylase inhibitor,which will serve as double-way intervention.Under the double-way intervention,we will observe the change of breast cancer cell cycle in different estrogen receptor condition,the influence on CyclinDl and CyclinA2,we will discuss the mechanism of histone deacetylation regulation on breast cancer cell,then we will evaluate the curative effect and side effect of histone deacetylase inhibitor alone and combined with chemotherapy drugs by animal model.Through this research,we hope that we can establish the breast cancer cell model transfected by HDAC1 plasimid and breast cancer animal model,which provides the experimental model for the correlation research;in theory,we can discuss the mechanism of histone deacetylation regulation on breast cancer cell in the view of CyclinDl and CyclinA2 expression.More importantly in the clinical practice aspect,the research will helps us to know the the quantity-effect relation and time-effect relation of histone deacetylase inhibitor for breast cancer cell,the animal model study will also provide experimental data for seeking new way to treat breast cancer and provide useful experimental reference for the histone-deacetylase-targeting-drug research and development of breast cancer.
[Methods]
1.Effect of histone deacetylase 1(HDAC1) on breast cancer cell cycle (Positive intervention)
1.1 To construct histone deacetylase 1(HDAC1) plasimid with HA tag (pcDNA3.1-HA- hdac1) by subcloning technique;
1.2 To make competence bacterium(E.coli) by CaCl_2 method;
1.3 To transform pcDNA3.1-HA-hdacl plasimid into competence bacterium (E.coli),harvest large number of pcDNA3.1-HA-hdacl plasimid,purify and check it by the enzyme digestion and DNA sequence;
1.4 To transfect the breast cancer cell with pcDNA3.1-HA-hdacl plasimid,detect the protein expression level with the Western bloting;
1.5 To examine the change of breast cancer cell cycle after transfection of pcDNA3.1-HA-hdac1 plasimid by using Flow cytometry(FCM).
2.Effect of histone deacetylase inhibitor(HDACi) on breast cancer cell cycle (Negative intervention)
2.1 To observe the change of breast cancer cell cycle after treated respectively by four kind of histone deacetylase inhibitor TSA,SAHA,CS055,MS-275 by MTT methods;(Screening inhibitor)
2.2 To examine the change of breast cancer cell cycle after treatment of different concentration of histone deacetylase inhibitor by using Flow cytometry(FCM).(Determination of inhibitor concentration)
3.Study of the influence of double-way histone deacetylation regulation on CyclinDl and CyclinA2 gene.
3.1 To transfect the breast cancer cell with pcDNA3.1 -HA-hdac1 plasimid; (Positive intervention)
3.2 To treat breast cancer cell by using histone deacetylase inhibitor; (Negative intervention)
3.3 To detect the Cyclin D1 and Cyclin A2 protein expression level with the Western bloting;
3.4 To examine the cell number which has Cyclin Dl and Cyclin A2 protein expression by using Flow cytometry(FCM).
4.Animal mode research of histone deacetylase inhibitor alone and combined with chemotherapy drugs on breast cancer cell.
4.1 To feed Balb/c-nu/nu(Crl:NU-Foxnlnu) female nude mouse(SPF grade),to construct transplanted tumor nude mouse model by injection of breast cancer cell suspension;
4.2 To design the histone deacetylase inhibitor concention gradient based on the above in vitro experiment dosage once more,gives the medicine through the tail intravenous injection,screen the best effective dose of this inhibitor in nude mouse,then conduct the next step experiment;
4.3 To divide nude mouse with transplanted tumor into 6 groups:control group, inhibitor group,taxol group,adriamycin group,taxol plus inhibitor group,adriamycin plus inhibitor group.To give related treatment factor separately.After 1 week,to get blood from the tail vein to carry on the blood cell analysis,and examine the items of the blood fat,the liver function and the kidney function.4 weeks later,to get the body weight,then pull the neck to execute the mouse,take the tumor out by surgery,get the wet weight of tumor.To count tumor growth inhibition rate and tumor volume.
[Results]
1.Effect of histone deacetylase 1(HDAC1) on breast cancer cell cycle (Positive intervention)
1.1 Construction and identification of histone deacetylase 1(HDAC1) plasimid with HA tag(pcDNA3.1-HA- hdac1):After successfully constructing of histone deacetylase 1(HDAC1) plasimid with HA tag(pcDNA3.1-HA- hdac1),we confirmed that hdacl DNA fragment is 1449bp(cutting position spot is BamH I/EcoR I)by the enzyme digestion and DNA sequence checking;Western bloting showed HDAC1 protein expression in both estrogen receptor positive and negative cell lines after transfection of HDAC1 plasimid;
1.2 Effect of histone deacetylase 1(HDAC1) on breast cancer cell cycle:after transfection of HDAC1 plasimid into cells,Flow cytometry(FCM)showed:for estrogen receptor positive cell line MCF-7,G0/G1 phase cell proportion dropped(40.31±2.15)%,S-phase cell proportion increased(17.98±1.87) %,P<0.05;for estrogen receptor negative cell line MDA-MB-435s,G0/G1 phase cell proportion dropped(41.22±2.27)%,S- phase cell proportion increased(16.70±2.33)%,P<0.05.Compared between the two cell lines, P>0.05。
2.Effect of histone deacetylase inhibitor(HDACi) on breast cancer cell cycle (Negative intervention)
2.1 Screening inhibitor:24h after treatment of TSA,SAHA,CS055 and MS-275,the cell demonstrated growth inhibition,the greatest inhibition happened at 48h after treatment;within four inhibitors,SAHA demonstrated strong inhibition ability (at the 48h time point,comparing SAHA group with TSA,CS055 and MS-275 group separately,P<0.05),for MCF-7 cell line,the inhibition of SAHA is (70.31±2.35)%;for MDA-MB-435s cell line,the inhibition of SAHA is (78.36±2.01)%。Compared between the two cell lines,P>0.05。
2.2 Inhibitor concentration:After 1.0,2.0,4.0,8.0,16.0μmol/L concentration gradient SAHA treating cell,4.0umol/L showed S-phase cell proportion dropping obviously(P<0.05),when the density further increased,the S-phase cell proportion did not continue dropping.
3.Study of the influence of double-way histone deacetylation regulation on CyclinDl and CyclinA2 gene.
3.1 Transfection of HDAC1 plasimid(Positive intervention):As to CyclinA2,cell line MCF-7 did not show change of cell number of CyclinA2 protein expression, for cell line MDA-MB-435S,cell number of CyclinA2 protein expression increased about 8%;Regarding to cyclinD1,cell number of CyclinD1 protein expression decresaed 10%in both MCF-7 and MDA-MB-435S cell lines.
3.2 Treatment of inhibitor SAHA(Negative intervention):In MCF-7 and MDA-MB-435S cell lines,cell number of CyclinA2 protein expression expression decresaed about 40%,cell number of CyclinD1 protein expression expression incresaed about 40%.
4.Animal mode research of histone deacetylase inhibitor alone and combined with chemotherapy drugs on breast cancer cell.
4.1 Screening the suitable dosage of SAHA in vivo:different dosage of SAHA was given to nude mouse with transplanted tumor,curative effect was observed as to tumor growth inhibition rate and tumor volume within 0.10～0.42 mg/kg dosage scope,the SAHA treatment effect presented the dosage-dependence relations.When the dosage rised from 0.42 mg/kg to 0.84 mg/kg,no further curative effect was observed.
4.2 Treatment factors were given to mouse:
4.2.1 Curative effects:tumor growth inhibition rate and tumor volume:compared with the control group,P<0.05,the difference has statistics significance; compared with each other,the taxol plus SAHA group showed superiority;
4.2.2 Side effects:①Body weight:the body weight dropped in the group containing taxol or adriamycin;②Blood cell analysis:the white blood cell number dropped in the group containing taxol or adriamycin,compared between SAHA alone and SAHA combined with chemotherapy drugs group,P>0.05;③Cholesterol,urea nitrogen and creatinine:Compared with the control group, P>0.05;④Blood serum glutamic-pyruvic transaminase:Compared with the control group,P<0.05;compared between SAHA alone and SAHA combined with taxol group,P<0.05;⑤Blood serum bilirubin:Compared with the control group,the level rised in the group containing taxol or adriamycin,P<0.05,but compared between SAHA alone and SAHA combined with chemotherapy drugs group,P>0.05.
[Conclusions]
1.The histone deacetylase 1(HDAC1) gene express in both estrogen receptor positive and negative breast cancer cell lines,its expression can promote cancer cell growth;
2.In vitro experiment,all of the four kind of histone deacetylase inhibitor(TSA,SAHA, CS055 and MS-275)can inhibite cell growth,in which SAHA is the strongest one, its inhibitory action is most obvious at 48h,suitable concentration is 4.0μmol/L;
3.Histone deacetylase inhibitor SAHA may regulate the expression of Cyclin A2 and Cyclin D1 gene,eventurally resulting of reduce of S-phase and M-phase cells, suppressing DNA duplication,synthesis and cell mitosis,causing the cell to be detained in the G1-phase,finally towards death,achieving the inhibition of breast cancer cell growth;
4.Histone deacetylation regulation was influenced by the hormone receptor condition slightly;
5.In breast cancer nude mouse animal model experiment,SAHA showed curitive effect,within 0.10 -0.42 mg/kg dosage scope,presenting the dosage dependence relations,0.42 mg/kg were most obvious,which is higher than in vitro experiment;
6.The curitive effect of SAHA alone is lower than chemotherapy drugs taxol or adriamycin,but combined with taxol or adriamycin may show synergistic effect;
7.SAHA leads little side effect to kidney function,blood cell and cholesterol,but has certain influence to the blood serum glutamic-pyruvic transaminase,this kind of influence does not increase while combined with chemotherapy drugs;
8.SAHA combined with chemotherapy drags may be good choice for breast cancer treatment.
引文
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1、Serge G,Jianyun Nie,Lin X,et al.Histone deacetylase 3 interacts with and deacetylates myocyte enhancer factor 2.Mol Cell Biol,2007,27(4):1280-1295.
2、Serge G,Annie T,Lin X,Qian Y,Kewei M,Jianyun Nie,et al.Control of MEF2transcriptional activity by coordinated phosphorylation and sumoylation.J.Biol.Chem.,2006,281(7):4423-4433.
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4、聂建云,刘馨,金从国,陈晓群,李佳,黄云超。组蛋白去乙酰化酶抑制剂对乳腺癌细胞株MCF-7增殖周期的影响。中国综合临床,2009,25(12):1238-1240.
5、聂建云,刘馨,金从国,陈晓群,李佳,黄云超。HDAC1对乳腺癌细胞MDA-MB-435s增殖影响的研究。山东医药,2009,49(32):20-22.
6、Xin Yi,Wei Wei,Sheng-Yu Wang,et al.Histone deacetylase inhibitor SAHA induces ERa degradation in breast cancer MCF-7 cells by CHIP-mediated ubiquitin pathway and inhibits survival signaling.Biochemical pharmacology,2008,75:1697-1705.
7、Raphael M,Vanessa D,Audrey C,et al.Histone deacetylase inhibition and estrogen signalling in human breast cancer cells.Biochemical Pharmacology,2004,68(4):1239-1246
8、Margueron R,Duong V,Bonnet S,et al.Histone deacetylase activity and estrogen receptor alpha levels modulate the transcriptional activity of partial antiestrogens.J Mol Endocrinol,2004,32(2):1957-1966.
9、Lorena T,Laura Viana,b,Monia B,Francesco G,et al.Epigenetic reprogramming of breast cancer cells by valproic acid occurs regardless of estrogen receptor status.The International Journal of Biochemistry & Cell Biology,2009,41:225-234.
10、Jiang Fan,Wen-Jin Yin,Jin-Song Lu,et al.ER negative breast cancer cells restore response to endocrine therapy by combination treatment with both HDAC inhibitor and DNMT inhibitor.J Cancer Res Clin Oncol,2008,134:883-890.
11、Kurtev V,Margueron R,Kroboth K,et al.Transcriptional regulation by the repressor of estrogen receptor activity via recruitment of histone deacetylases.J Biol Chem,2004,279(21):24834-24843.
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