CARM1在乳腺癌中的表达及其对MDR1介导的多药耐药的调节
摘要
[研究背景]
浸润性乳腺癌是女性最常见的恶性肿瘤,在全球范围占女性癌症的23%。乳腺癌发病率仍在逐年升高,严重危害世界女性健康。化学治疗是治疗乳腺癌的主要手段之一,但是癌细胞的对化疗药物的多药耐药(multidrug resistance, MDR)严重影响化疗药的有效性。多药耐药是指在药物诱导后,肿瘤对一系列结构、靶点和作用机制不同的药物均产生了耐药性。
P-糖蛋白(P-glycoprotein, P-gp)是由多药耐药基因1(MDRl)编码,是最重要的药物转运蛋白,是恶性肿瘤原发性和继发性耐药的主要原因,与细胞内药物浓度及耐药程度密切相关。目前报道显示许多抗肿瘤药物,包括多柔比星、紫杉醇等均为P-糖蛋白的作用底物。MDR1基因在人体恶性肿瘤中广泛表达,约50%的乳腺癌的多药耐药与P-糖蛋白的过表达相关。即使在低表达的肿瘤,治疗后也可产生P-糖蛋白的高表达,恶性肿瘤化疗后P-糖蛋白表达率高达88%。多药耐药导致化疗失败、肿瘤转移、患者生存期缩短以及肿瘤治疗成本的显著增加。对于P－gp高表达的恶性肿瘤,可使用MDR1逆转剂,以提高肿瘤细胞对化疗药物的敏感性。目前经常应用化学合成的抑制剂以增加肿瘤细胞的敏感性,但是在达到有效浓度时也具有较大的毒性。这促使人们更深入地研究MDR1的表达调节机制。
研究表明MDR1的表达主要由类固醇和异生素受体(steroid and xenobiotic receptor, SXR)的调节。SXR是一种细胞核受体(nuclear receptor, NR),核受体的转录调节作用需要和多种共激活因子协同完成。与相应配体结合后,经过一系列复杂的过程,核受体会募集几种不同的共激活因子到靶基因的启动子区,形成转录激活复合物。共激活因子有的通过蛋白质-蛋白质的相互作用行使功能,能够促进或抑制其它共激活因子或特定的转录元件的募集；有的可通过酶活性来催化相关蛋白的翻译后修饰。在核受体介导的转录调节中,翻译后修饰起着重要的作用,具有酶活性的共激活因子的翻译后修饰在配体触发的转录调控中是必不可少的。在SXR对MDR1的调控中,SXR与相应药物配体结合后,在p160蛋白家族介导下,激活定位于MDR1基因启动子的异生素反应元件(xenobiotic-response elements, XREs),启动MDR1的转录。在这个过程中,P160共激活因子家族直接与核受体结合,是募集其他共激活因子的重要支架。但是目前仍不清楚具体还有那些共激活因子参与了SXR对MDR1的转录激活过程,这尚需深入研究。
精氨酸甲基化是一种近年发现的转录后修饰,由蛋白精氨酸甲基转移酶(protein argininemethyltransferase, PRMTs)家族催化。在哺乳动物体内,迄今共发现11个PRMTs家族成员；根据酶催化产物的结构,可将PRMTs分为Ⅰ型和Ⅱ型两大类。Ⅰ型PRMTs (PRMT1, PRMT4, PRMT3和PRMT6)形成非对称二甲基精氨酸,而Ⅱ型酶催化形成对称性二甲基精氨酸。PRMT4又称为共激活相关精氨酸甲基化转移酶1(coactivator-associated arginine methyltransferase1, CARM1),最初是在酵母双杂交筛选发现的,是p160共激活因子家族的结合蛋白。后来研究逐渐发现CARM1在细胞内具有多方面的功能,特别在控制细胞周期和生存方面。CARM1能够甲基化组蛋白和多种非组蛋白,是多种核受体转录激活的共激活因子,也可以共激活其它多种转录因子。
目前关于CARM1在恶性肿瘤中的表达情况的研究并不多,已有报道CARM1在前列腺癌和大肠癌中高表达并且与预后差的指标有关。少数研究报道了CARM1在人乳腺癌组织的异常表达。但是目前的研究存在矛盾之处。El MessaoudiS检测了81例乳腺癌组织的CARM1mRNA表达水平,发现CARM1在组织学三级的乳腺癌中显著升高。但是也有研究表明在ER阳性和无淋巴结转移的乳腺癌中,CARM1的表达与肿瘤的组织学分级之间呈负相关性。还有研究报道CARM1过表达仅见于少数乳腺癌患者(27%)。上述研究提示CARM1是一个可能是影响乳腺癌进展和预后的重要因素。然而,这些研究只研究了少数病例或者只研究CARM1在乳腺癌特殊亚型中的表达。目前还不清楚CARM1表达与临床病理特征,分子分型和预后之间的关系。
目前虽然已有研究证实CARM1是许多核受体的共激活因子,例如雌激素受体、雄激素受体、糖皮质激素受体和甲状腺激素受体等,但是还没有研究证实CARM1参与了核受体SXR对MDR1的转录激活过程。SXR对于MDR1的转录激活过程需要p160蛋白家族参与,而CARM1被证明是p160家族的转录辅激活因子,p160家族的三个成员都是CARM1的天然底物。综上所述,CARM1在p160参与的数种核受体转录激活中起着重要作用,极有可能参加了SXR对MDR1的调节。研究CARM1与SXR和MDR1的相关性,探讨其参与肿瘤多药耐药的调控机制,或为多药耐药逆转提供新的治疗靶点。
本研究首先应用免疫组织化学染色的方法,检测了247未经治疗的原发性乳腺浸润性癌组织中CARM1、ER、PR、HER2、p53、Ki-67指数和MDR1/P-gp的表达情况。进而检测了乳腺癌敏感细胞株MCF-7和多药耐药细胞株MCF-7/ADM中的CARM1的表达,结果表明,在多药耐药细胞中,CARM1mRNA的水平和蛋白水平均显著高于敏感细胞,提示CARM1在MDR1介导的乳腺癌细胞的多药耐药的过程中可能具有潜在作用。因此,在本研究中设计并合成针对CARM1基因的双链干扰RNA序列(siRNA),将其定向插入到质粒载体中,经酶切和测序鉴定后,转染至乳腺癌耐药细胞株来沉默CARM1表达,以期下调MDR1/P-gp的表达,从而逆转MDR1介导的多药耐药；同时将含有CARM1全长DNA的质粒转染至敏感细胞株中,观察CARM1外源性过表达对MDR1/P-gp的表达和功能的影响；从而初步探讨CARM1参与调控MDR1的可能的机制。
[研究方法]
1.采用免疫组织化学链霉菌抗生物素蛋白-过氧化物酶复合物法Streptavidin-Peroxidasecomplex method)检测247例未经治疗的原发性乳腺浸润性癌组织中CARM1、ER、PR、HER2、p53、Ki-67指数和MDR1的表达情况,并分析了CARM1的表达与乳腺癌临床病理特征、常用分子指标和分子亚型之间的关系,同时分析了CARM1与和MDR1之间的相关性。
2.以本实验室培养的乳腺癌敏感细胞系MCF-7和多药耐药细胞系MCF-7/ADM为研究对象,用RT-PCR和Western Blot方法分别检测CARM1及MDR1/P-gp的mRNA和蛋白表达情况。
3.设计并合成靶向CARM1基因的双链干扰RNA序列,以和作为阴性对照的非靶向干扰序列,将其定向插入到质粒载体pSUPER.neo+GFP中,构建稳定表达的质粒载体pSUPER-siCARM1和pSUPER-siNotargeto经过限制性内切酶切和测序鉴定,确保插入正确后,通过细菌培养大量扩增。
4.哺乳动物表达质粒pSG5.HA-CARM1和pSG5.HA由Michael R. Stallcup教授(美国南加利福尼亚大学)惠赠.将CARM1全长DNA经限制性内切酶酶切后,插入到pEGFP-C1质粒中,得到重组质粒pEGFP-C1-CARM1。经过限制性内切酶切和测序鉴定,确保插入正确后,通过细菌培养大量扩增。
5.分别转染CARM1干扰质粒载体和外源性过表达质粒至多药耐药细胞和敏感细胞中；经过48h培养,采用RT-PCR检测各实验组细胞中CARM1mRNA和MDR1mRNA的表达情况,应用Western blot检测CARM1蛋白和P-糖蛋白表达情况,应用MTT法检测各组细胞对阿霉素的半数细胞抑制浓度(IC50)和相对耐药指数(RR)的改变,评价CARM1基因沉默和外源性过表达后对乳腺癌细胞的多药耐药性的影响。
[实验结果]
1.免疫组化：CARM1染色可见于细胞核和细胞浆。与其周围良性上皮相比,腺癌的表达显著增高。CARM1过表达与以下指标显著相关：低发病年龄、较高的组织学分级、雌激素受体(ER)和孕激素受体(PR)阴性、HER2和p53过表达、以及高Ki-67指数。在乳腺癌的分子亚型中,HER2亚型中CARM1表达率最高(69.6%),其次是luminal B亚型(59.6%)和TN亚型(57.1%),luminal A亚型的表达率最低(41.3%)。在乳腺癌组织中,MDR1/P-gp表达率为45.7%,CARM1的表达与MDR1/P-gp表达呈显著正相关。
2.对本实验室培养的乳腺癌敏感细胞系和多药耐药细胞系的检测结果表明,在多药耐药细胞MCF-7/ADM中,CARM1的mRNA水平和蛋白水平均较敏感细胞MCF-7显著升高；MCF-7/ADM细胞中高表达MDR1/P-gp,而敏感株MCF-7几乎不表达。
3.转染后48h,收集细胞,应用半定量RT-PCR检测转染pSUPER-siCARM1的耐药细胞中CARM1和MDR1mRNA的表达情况,结果显示：CARM1干扰组的CARM1及MDR1mRNA水平均较对照组(转染非靶向性siRNA)明显降低；Western blot同样显示,CARM1和MDR1/P-gp的蛋白表达水平在CARM1干扰组细胞中显著低于对照组细胞；MTT法检测癌细胞对阿霉素的耐受性,发现CARM1干扰组细胞对阿霉素的IC50明显降低,相对耐药指数显著下降,明显逆转了癌细胞的耐药性。
4.转染48h后,应用半定量RT-PCR检测转染pEGFP-C1-CARM1的敏感细胞系MCF-7中CARM1和MDR1mRNA水平的表达情况,结果表明,外源性过表达CARM1组的CARM1mRNA和蛋白水平均较对照组均明显升高,但是MDR1/P-gp的mRNA和蛋白水平无显著性升高；MTT显示外源性过表达CARM1组对阿霉素的耐受性无明显变化。
[结论]
1.免疫组化结果表明,CARM1在乳腺癌组织中的表达较周围良性上皮细胞明显升高。定位于癌细胞核的CARM1过表达与低发病年龄、多发性或多中心性肿瘤、高组织学级别、雌激素和孕激素受体阴性、HER2过表达、p53过表达和高Ki-67指数有关。CARM1在不同的分子亚型之间表达水平不同,提示在不同分子亚型中,CARM1可能参与不同的机制调节肿瘤生长。
2.在乳腺癌组织中,CARM1蛋白的表达与MDR1/P-gp的表达呈显著正相关。在乳腺癌细胞多药耐药细胞株中,CARM1与MDR1均呈高表达,提示CARM1与MDR1介导的获得性多药耐药之间具有相关性。
3.在乳腺癌细胞多药耐药细胞株中,干扰CARM1能够抑制MDR1的表达,使得癌细胞的多药耐药性显著降低,从而逆转多药耐药,表明CARM1参与了MDR1/P-gp调节过程；
4.在乳腺癌细胞敏感细胞株中,外源性过表达CARM1未引起MDR1/P-gp的表达和功能的改变,提示CARM1可能是核受体介导的MDR1/P-gp转录激活过程中的辅激活因子。
5. CARM1可调控MDR1/P-gp介导的乳腺癌细胞多药耐药,可能是潜在的可预知乳腺癌化疗敏感性的指标,可能有助于个性化治疗,并为逆转多药耐药的提供新的靶点。
[Background]
Worldwide, invasive breast cancer is the most common cancer in female and accounts for23%of female cancers. the incidence rate is still increasing year by year. Chemotherapy is one of the primary means in breast cancer treatment. However, the effectiveness of chemotherapy drugs is decreased in case of the multidrug resistance (MDR) of cancer cells. The multidrug resistance refers to that when a kind of tumor become resistant to one drug, it would also become resistant to other anti-cancer agents which even have different structures,target sites, or mechanisms.
The P-glycoprotein (P-gp), encoded by multidrug resistance gene1(MDR1), is the most important drug transporters. P-gp is a major cause of primary drug resistance, and is closely related with drug concentration and drug resistant degree in cancer cells. It is reported that many anticancer drugs, such as doxorubicin and paclitaxel, are all substrates of P-gp. MDR1gene is widely expressed in human malignancies and covers about50%of multidrug resistances in breast cancer. Even tumors with low P-pg expression would produce a high level of P-glycoprotein after treatment. P-glycoprotein expression rate is up to88%after chemotherapy in malignant tumors. MDR is one of the major reasons which causes failure of chemotherapy, tumor metastasis, shortened survival, and increased costs of cancer treatment. Chemical syntheses of inhibitors are used in P-gp overexpression malignancies in order to increase the sensitivity of chemotherapeutic drugs in tumor cells and prolong clinical remission. However, chemical drugs at therapeutic concentrations often causeundesired toxicity.It is necessary to furtherresearchthe mechanism of MDR1/P-gp expression and regulation.
Recent studies have revealed that the nuclear receptor, steroid and xenobiotic receptor (SXR), is the master transcriptional regulators of MDR1gene expression.In the transcriptional regulation of nuclear receptors, manycoregulators are needed and the coregulators play critical roles in regulating chromatin conformation and regulating the recruitment and activation ofRNApolymerase Ⅱ. The nuclear receptors can recruit several different coactivators to the promoter region of target genes after binding with ligands. Some coregulators function by protein-protein interactions, forexampleby facilitating or inhibiting recruitment of other coregulators or specific components of the transcription machinery. Other coregulators are enzymes that catalyze posttranslational modifications to histones, nuclear receptors, other coregulators, and components of signal transduction pathways. Thus, posttranslational modifications of many components of the basal and regulatory transcription machinery also play major roles in nuclear receptor-mediated transcriptional regulation. As for SXR, after binding to a variety of xenobiotics, it can activate the xenobiotic-response elements (XREs), which locate in the MDR1gene promoter, and stimulates transcription. P160family is involved in this process andcan bind directly to SXR. P160family functions as a scaffoldto recruit other coactivators. However, it still remainsunknownwhatelse factors are involved in activation and regulation of SXR/MDR1pathway.
Methylation of histones by protein arginine methyltransferases (PRMTs) is increasingly being acknowledged as an important aspect for the dynamic regulation of gene expression. The11mammalian PRMTs fall into two predominant classes, based on the types of methylarginine products they produce. Type Ⅰ enzymes (PRMT1, PRMT3, PRMT4/CARM1, PRMT6, and PRMT8) form monomethylarginine and asymmetric dimethylarginine, and type Ⅱ enzymes (PRMT5, PRMT7, and FBXO11) form monomethylarginine and symmetric dimethylarginine. PRMT4, namely coactivator-associated arginine methyltransferase1(CARM1) is initially identified as a SRC-2bindingprotein in a yeast two-hybrid screening. There are increasing evidences indicate CARM1plays pleiotropic roles in cell proliferation and survival.
Some researchers had investigated the expression of CARM1in many kinds of malignant tumors. Aberrant expression of CARM1has been linked to human breast cancer tissue in a few reports; however, current studies are contradictory and incomplete. The mRNA level of CARM1was found to be elevated in grade3breast tumors in a cohort of81human breast carcinomas of various types. While another study demonstrated there was inverse correlation between CARM1expression and tumor grade in ER+and LN-breast cancer cases. Kim YR et al reported CARM1overexpression was noted only in small number of breast cancer patients (27%). All these reports suggest CARM1is an important factor involved in progression and may affect prognostication of breast cancer. However, many of these studies were limited either by low n values of breast cancer patients or by a special tumor type. It still remains unclear whether CARM1expression is correlated with clinicopathological features, molecular subtype and prognosis.
CARM1functions as a coactivator for many nuclear receptors, such as the estrogen receptor (ER), androgen receptor (AR), the glucocorticoid receptor, and the thyroid receptor. However, it is still unknown whether CARM1is involved in the transcriptional regulation of MDR1. The regulation of SXR on MDR1requires the anticipation of p160protein family. While CARM1has been showed to be a coactivator of p160family, all members of p160family are natural substrates of CARM1. In summary, because CARM1activation plays an important role in the transcriptional regulation of nuclear receptor and p160, we presume that CARM1might be involved in the transcriptional activation of MDR1; probably through SXRpathway. It is necessary to investigate the correlation between CARM1, SXR and MDR1and the possible mechanism. This might contribute to understand the reversal of multidrug resistance and might provide new potential therapeutic targets.
In this study, we first examined expression of CARM1, ER, PR, HER2, p53, Ki-67index and MDR1in247cases of untreated primary invasive ductal carcinoma by immunohistochemistry. Furthermore, We detected the expression of CARM1in the breast cancer cell lines MCF-7and the multidrug resistant subline MCF-7/ADM. The results showed a higher expression of CARM1and MDR1/P-gp on both mRNA and protein levels in MCF-7/ADM cells, compared with the sensitive MCF-7cell lines.These results suggested the potential roles of CARM1in the development of multidrugresistance in breast cancer cells.Therefore, in this study, we proposed that the silencing of CARM1by plasmid-mediated expression of small interference RNA (siRNA) might result in the down-regulation of MDRl/P-gp, and thus reverse multidrug resistance in MDR cells. Anda full-length cDNA of CARM1mediated by plasmids was also transfected into MCF-7to investigate whetherexogenous overexpression of CARM1would improve drug resistance.
[Methods]
1. We examined the expression of CARM1, ER, PR, HER2, p53, Ki-67index and MDR1by immunohistochemistry of streptavidin peroxidase complex method. Then, we analyzed the relationship between CARM1, the clinical pathological characters, universal molecular markers and molecular subtypes respectively, as well as the correlation between CARM1and MDRl/P-gp.
2. Using RT-PCR and Western blot, we examined the expression of CARMl in breast cancer cell lines MCF-7and the multidrug resistant subline MCF-7/ADM.
3. Small hairpin siRNA sequences targeted at CARM1and negative controls, non-targeting siRNAs sequences, were designed and synthesized as64oligonucleotides. After annealed, they were cloned into the pSUPER. neo+GFP expression vector respectively. After comfirmed by enzyme digestion and DNA sequencing, the recombinant plasmids were amplified in bacteria and extracted subsequently.
4. The mammalian expression plasmid of pSG5.HA-CARM1was generously provided by Michael R. Stallcup (University of Southern California). We constructed pEGFP-C1-CARM1by insertion of CARM1which was cut out from pSG5.HA-CARM1with EcoRIinto pEGFP-C1plasmids. After comfirmed by enzyme digestion and DNA sequencing, the recombinant plasmids were amplified in bacteria and extracted subsequently.
5. The MDR cells ADM were transfected with pSUPER-siFZDl and pSUPER-siNotarget respectively. And sensitive cells MCF-7were transfected with pEGFP-C1-CARM1.After another48h culture, mRNA and protein expression of CARM1and MDRl/P-gp were examined by RT-PCR and Western blot. MTT assay was used to assess the effect of CARM1silencing and exogenous overexpression of CARM1on ADM and MCF-7cells respectively to doxorubicin.
[Results]
1. In invasive breast cancer tissues, CARM1expression was increased in invasive breast cancer cells compared with adjacent benign epithelium.The increased expression was observed in the cytoplasm and/or the nucleus Nuclear CARM1expression was associated with a younger age at diagnosis; multi-center origin or multiple tumors; a higher tumor grade; a higher rate of HER2, p53, and Ki-67expression; and a lower rate of ER and PR expression. We also found that the rate of CARM1expression was significantly different among different molecular subtypes of breast cancer. We showed that in the HER2subtype, the nuclear expression of CARM1was the highest (69.6%), followed by the luminal B (59.6%) and basal type (57.1%). The luminal A type showed the lowest percentage of cells with CARM1nuclear expression (41.3%). As to MDR1, the percentage of P-Gpexpressing was45.7%, and the expression of CARM1was positively related to that of P-gpexpression.
2. In MCF/ADM cells, CARM1was found to havehigher mRNA and protein levels in relation to MDRl/P-gp expression, compared with the sensitive cell line MCF-7.
3. The effects of CARM1interferencein ADM were verified by semi-quantitative RT-PCR. The level of CARM1and MDR1mRNA was down-regulated significantly in comparison with the control.Western blotanalysesindicated that CARM1and MDRl/P-gp were down-regulated in response to CARM1interference. MTT assay showed thatIC50value of doxorubicin wasdecreased remarkably after CARM1interferencein ADM cells.
4. The effects of CARM1exogenous overexpression in MCF-7cells were verified by semi-quantitative RT-PCR. The level of CARM1mRNA was up-regulated significantly in comparison with the control, while MDR1mRNA was notalterednotably.Western blotanalysesindicated that CARM1wasup-regulated afterexogenous overexpression of CARM1, whileMDR1/P-gp was not altered significantly. MTT assay also showed MCF-7IC50valueof doxorubicin did not changeremarkably in response to CARM1exogenous overexpression.
[Conclusions]
1. CARM1expression was increased in invasive breast cancer cells compared with adjacent benign epithelium. Nuclear CARM1expression was associated with a younger age at diagnosis; multi-center origin or multiple tumors; a higher tumor grade; a higher rate of HER2, p53, and Ki-67expression; and a lower rate of ER and PR expression. All of these predictors were clinicpathologic parameters that correlate with poor prognosis. We also found that the rate of CARM1expression was significantly different among different molecular subtypes of breast cancer.
2. In invasive breast cancer tissues, the expression of CARM1was positively related to that of MDR1. CARM1was also overexpressed in the multidrug resistant breast cancer cells, consistent with MDR1/P-gp expression.
3. In the multidrug resistant breast cancer cells, the silencing of CARM1decreased MDR1expression and reversed the multidrug resistance. It was indicated that CARM1was involved in the regulation of MDRl/P-gp.
4. The exogenous overexpressionofCARMl in breast cancer sensitive cells did not change MDR1/P-gp expression and function.These resultssupportedthe hypothesis that CARM1might be a secondary coactivator in SXR/MDR1pathway.
5. CARM1can modulate multidrug resistance through regulating the MDR1,probably through SXRpathway.CARM1is possible to be identified as a new molecular marker to predict multidrug resistance for personalized treatment and new latent target for MDR reversing in breast cancer cells.
浸润性乳腺癌是女性最常见的恶性肿瘤,在全球范围占女性癌症的23%。乳腺癌发病率仍在逐年升高,严重危害世界女性健康。化学治疗是治疗乳腺癌的主要手段之一,但是癌细胞的对化疗药物的多药耐药(multidrug resistance, MDR)严重影响化疗药的有效性。多药耐药是指在药物诱导后,肿瘤对一系列结构、靶点和作用机制不同的药物均产生了耐药性。
P-糖蛋白(P-glycoprotein, P-gp)是由多药耐药基因1(MDRl)编码,是最重要的药物转运蛋白,是恶性肿瘤原发性和继发性耐药的主要原因,与细胞内药物浓度及耐药程度密切相关。目前报道显示许多抗肿瘤药物,包括多柔比星、紫杉醇等均为P-糖蛋白的作用底物。MDR1基因在人体恶性肿瘤中广泛表达,约50%的乳腺癌的多药耐药与P-糖蛋白的过表达相关。即使在低表达的肿瘤,治疗后也可产生P-糖蛋白的高表达,恶性肿瘤化疗后P-糖蛋白表达率高达88%。多药耐药导致化疗失败、肿瘤转移、患者生存期缩短以及肿瘤治疗成本的显著增加。对于P－gp高表达的恶性肿瘤,可使用MDR1逆转剂,以提高肿瘤细胞对化疗药物的敏感性。目前经常应用化学合成的抑制剂以增加肿瘤细胞的敏感性,但是在达到有效浓度时也具有较大的毒性。这促使人们更深入地研究MDR1的表达调节机制。
研究表明MDR1的表达主要由类固醇和异生素受体(steroid and xenobiotic receptor, SXR)的调节。SXR是一种细胞核受体(nuclear receptor, NR),核受体的转录调节作用需要和多种共激活因子协同完成。与相应配体结合后,经过一系列复杂的过程,核受体会募集几种不同的共激活因子到靶基因的启动子区,形成转录激活复合物。共激活因子有的通过蛋白质-蛋白质的相互作用行使功能,能够促进或抑制其它共激活因子或特定的转录元件的募集；有的可通过酶活性来催化相关蛋白的翻译后修饰。在核受体介导的转录调节中,翻译后修饰起着重要的作用,具有酶活性的共激活因子的翻译后修饰在配体触发的转录调控中是必不可少的。在SXR对MDR1的调控中,SXR与相应药物配体结合后,在p160蛋白家族介导下,激活定位于MDR1基因启动子的异生素反应元件(xenobiotic-response elements, XREs),启动MDR1的转录。在这个过程中,P160共激活因子家族直接与核受体结合,是募集其他共激活因子的重要支架。但是目前仍不清楚具体还有那些共激活因子参与了SXR对MDR1的转录激活过程,这尚需深入研究。
精氨酸甲基化是一种近年发现的转录后修饰,由蛋白精氨酸甲基转移酶(protein argininemethyltransferase, PRMTs)家族催化。在哺乳动物体内,迄今共发现11个PRMTs家族成员；根据酶催化产物的结构,可将PRMTs分为Ⅰ型和Ⅱ型两大类。Ⅰ型PRMTs (PRMT1, PRMT4, PRMT3和PRMT6)形成非对称二甲基精氨酸,而Ⅱ型酶催化形成对称性二甲基精氨酸。PRMT4又称为共激活相关精氨酸甲基化转移酶1(coactivator-associated arginine methyltransferase1, CARM1),最初是在酵母双杂交筛选发现的,是p160共激活因子家族的结合蛋白。后来研究逐渐发现CARM1在细胞内具有多方面的功能,特别在控制细胞周期和生存方面。CARM1能够甲基化组蛋白和多种非组蛋白,是多种核受体转录激活的共激活因子,也可以共激活其它多种转录因子。
目前关于CARM1在恶性肿瘤中的表达情况的研究并不多,已有报道CARM1在前列腺癌和大肠癌中高表达并且与预后差的指标有关。少数研究报道了CARM1在人乳腺癌组织的异常表达。但是目前的研究存在矛盾之处。El MessaoudiS检测了81例乳腺癌组织的CARM1mRNA表达水平,发现CARM1在组织学三级的乳腺癌中显著升高。但是也有研究表明在ER阳性和无淋巴结转移的乳腺癌中,CARM1的表达与肿瘤的组织学分级之间呈负相关性。还有研究报道CARM1过表达仅见于少数乳腺癌患者(27%)。上述研究提示CARM1是一个可能是影响乳腺癌进展和预后的重要因素。然而,这些研究只研究了少数病例或者只研究CARM1在乳腺癌特殊亚型中的表达。目前还不清楚CARM1表达与临床病理特征,分子分型和预后之间的关系。
目前虽然已有研究证实CARM1是许多核受体的共激活因子,例如雌激素受体、雄激素受体、糖皮质激素受体和甲状腺激素受体等,但是还没有研究证实CARM1参与了核受体SXR对MDR1的转录激活过程。SXR对于MDR1的转录激活过程需要p160蛋白家族参与,而CARM1被证明是p160家族的转录辅激活因子,p160家族的三个成员都是CARM1的天然底物。综上所述,CARM1在p160参与的数种核受体转录激活中起着重要作用,极有可能参加了SXR对MDR1的调节。研究CARM1与SXR和MDR1的相关性,探讨其参与肿瘤多药耐药的调控机制,或为多药耐药逆转提供新的治疗靶点。
本研究首先应用免疫组织化学染色的方法,检测了247未经治疗的原发性乳腺浸润性癌组织中CARM1、ER、PR、HER2、p53、Ki-67指数和MDR1/P-gp的表达情况。进而检测了乳腺癌敏感细胞株MCF-7和多药耐药细胞株MCF-7/ADM中的CARM1的表达,结果表明,在多药耐药细胞中,CARM1mRNA的水平和蛋白水平均显著高于敏感细胞,提示CARM1在MDR1介导的乳腺癌细胞的多药耐药的过程中可能具有潜在作用。因此,在本研究中设计并合成针对CARM1基因的双链干扰RNA序列(siRNA),将其定向插入到质粒载体中,经酶切和测序鉴定后,转染至乳腺癌耐药细胞株来沉默CARM1表达,以期下调MDR1/P-gp的表达,从而逆转MDR1介导的多药耐药；同时将含有CARM1全长DNA的质粒转染至敏感细胞株中,观察CARM1外源性过表达对MDR1/P-gp的表达和功能的影响；从而初步探讨CARM1参与调控MDR1的可能的机制。
[研究方法]
1.采用免疫组织化学链霉菌抗生物素蛋白-过氧化物酶复合物法Streptavidin-Peroxidasecomplex method)检测247例未经治疗的原发性乳腺浸润性癌组织中CARM1、ER、PR、HER2、p53、Ki-67指数和MDR1的表达情况,并分析了CARM1的表达与乳腺癌临床病理特征、常用分子指标和分子亚型之间的关系,同时分析了CARM1与和MDR1之间的相关性。
2.以本实验室培养的乳腺癌敏感细胞系MCF-7和多药耐药细胞系MCF-7/ADM为研究对象,用RT-PCR和Western Blot方法分别检测CARM1及MDR1/P-gp的mRNA和蛋白表达情况。
3.设计并合成靶向CARM1基因的双链干扰RNA序列,以和作为阴性对照的非靶向干扰序列,将其定向插入到质粒载体pSUPER.neo+GFP中,构建稳定表达的质粒载体pSUPER-siCARM1和pSUPER-siNotargeto经过限制性内切酶切和测序鉴定,确保插入正确后,通过细菌培养大量扩增。
4.哺乳动物表达质粒pSG5.HA-CARM1和pSG5.HA由Michael R. Stallcup教授(美国南加利福尼亚大学)惠赠.将CARM1全长DNA经限制性内切酶酶切后,插入到pEGFP-C1质粒中,得到重组质粒pEGFP-C1-CARM1。经过限制性内切酶切和测序鉴定,确保插入正确后,通过细菌培养大量扩增。
5.分别转染CARM1干扰质粒载体和外源性过表达质粒至多药耐药细胞和敏感细胞中；经过48h培养,采用RT-PCR检测各实验组细胞中CARM1mRNA和MDR1mRNA的表达情况,应用Western blot检测CARM1蛋白和P-糖蛋白表达情况,应用MTT法检测各组细胞对阿霉素的半数细胞抑制浓度(IC50)和相对耐药指数(RR)的改变,评价CARM1基因沉默和外源性过表达后对乳腺癌细胞的多药耐药性的影响。
[实验结果]
1.免疫组化：CARM1染色可见于细胞核和细胞浆。与其周围良性上皮相比,腺癌的表达显著增高。CARM1过表达与以下指标显著相关：低发病年龄、较高的组织学分级、雌激素受体(ER)和孕激素受体(PR)阴性、HER2和p53过表达、以及高Ki-67指数。在乳腺癌的分子亚型中,HER2亚型中CARM1表达率最高(69.6%),其次是luminal B亚型(59.6%)和TN亚型(57.1%),luminal A亚型的表达率最低(41.3%)。在乳腺癌组织中,MDR1/P-gp表达率为45.7%,CARM1的表达与MDR1/P-gp表达呈显著正相关。
2.对本实验室培养的乳腺癌敏感细胞系和多药耐药细胞系的检测结果表明,在多药耐药细胞MCF-7/ADM中,CARM1的mRNA水平和蛋白水平均较敏感细胞MCF-7显著升高；MCF-7/ADM细胞中高表达MDR1/P-gp,而敏感株MCF-7几乎不表达。
3.转染后48h,收集细胞,应用半定量RT-PCR检测转染pSUPER-siCARM1的耐药细胞中CARM1和MDR1mRNA的表达情况,结果显示：CARM1干扰组的CARM1及MDR1mRNA水平均较对照组(转染非靶向性siRNA)明显降低；Western blot同样显示,CARM1和MDR1/P-gp的蛋白表达水平在CARM1干扰组细胞中显著低于对照组细胞；MTT法检测癌细胞对阿霉素的耐受性,发现CARM1干扰组细胞对阿霉素的IC50明显降低,相对耐药指数显著下降,明显逆转了癌细胞的耐药性。
4.转染48h后,应用半定量RT-PCR检测转染pEGFP-C1-CARM1的敏感细胞系MCF-7中CARM1和MDR1mRNA水平的表达情况,结果表明,外源性过表达CARM1组的CARM1mRNA和蛋白水平均较对照组均明显升高,但是MDR1/P-gp的mRNA和蛋白水平无显著性升高；MTT显示外源性过表达CARM1组对阿霉素的耐受性无明显变化。
[结论]
1.免疫组化结果表明,CARM1在乳腺癌组织中的表达较周围良性上皮细胞明显升高。定位于癌细胞核的CARM1过表达与低发病年龄、多发性或多中心性肿瘤、高组织学级别、雌激素和孕激素受体阴性、HER2过表达、p53过表达和高Ki-67指数有关。CARM1在不同的分子亚型之间表达水平不同,提示在不同分子亚型中,CARM1可能参与不同的机制调节肿瘤生长。
2.在乳腺癌组织中,CARM1蛋白的表达与MDR1/P-gp的表达呈显著正相关。在乳腺癌细胞多药耐药细胞株中,CARM1与MDR1均呈高表达,提示CARM1与MDR1介导的获得性多药耐药之间具有相关性。
3.在乳腺癌细胞多药耐药细胞株中,干扰CARM1能够抑制MDR1的表达,使得癌细胞的多药耐药性显著降低,从而逆转多药耐药,表明CARM1参与了MDR1/P-gp调节过程；
4.在乳腺癌细胞敏感细胞株中,外源性过表达CARM1未引起MDR1/P-gp的表达和功能的改变,提示CARM1可能是核受体介导的MDR1/P-gp转录激活过程中的辅激活因子。
5. CARM1可调控MDR1/P-gp介导的乳腺癌细胞多药耐药,可能是潜在的可预知乳腺癌化疗敏感性的指标,可能有助于个性化治疗,并为逆转多药耐药的提供新的靶点。
[Background]
Worldwide, invasive breast cancer is the most common cancer in female and accounts for23%of female cancers. the incidence rate is still increasing year by year. Chemotherapy is one of the primary means in breast cancer treatment. However, the effectiveness of chemotherapy drugs is decreased in case of the multidrug resistance (MDR) of cancer cells. The multidrug resistance refers to that when a kind of tumor become resistant to one drug, it would also become resistant to other anti-cancer agents which even have different structures,target sites, or mechanisms.
The P-glycoprotein (P-gp), encoded by multidrug resistance gene1(MDR1), is the most important drug transporters. P-gp is a major cause of primary drug resistance, and is closely related with drug concentration and drug resistant degree in cancer cells. It is reported that many anticancer drugs, such as doxorubicin and paclitaxel, are all substrates of P-gp. MDR1gene is widely expressed in human malignancies and covers about50%of multidrug resistances in breast cancer. Even tumors with low P-pg expression would produce a high level of P-glycoprotein after treatment. P-glycoprotein expression rate is up to88%after chemotherapy in malignant tumors. MDR is one of the major reasons which causes failure of chemotherapy, tumor metastasis, shortened survival, and increased costs of cancer treatment. Chemical syntheses of inhibitors are used in P-gp overexpression malignancies in order to increase the sensitivity of chemotherapeutic drugs in tumor cells and prolong clinical remission. However, chemical drugs at therapeutic concentrations often causeundesired toxicity.It is necessary to furtherresearchthe mechanism of MDR1/P-gp expression and regulation.
Recent studies have revealed that the nuclear receptor, steroid and xenobiotic receptor (SXR), is the master transcriptional regulators of MDR1gene expression.In the transcriptional regulation of nuclear receptors, manycoregulators are needed and the coregulators play critical roles in regulating chromatin conformation and regulating the recruitment and activation ofRNApolymerase Ⅱ. The nuclear receptors can recruit several different coactivators to the promoter region of target genes after binding with ligands. Some coregulators function by protein-protein interactions, forexampleby facilitating or inhibiting recruitment of other coregulators or specific components of the transcription machinery. Other coregulators are enzymes that catalyze posttranslational modifications to histones, nuclear receptors, other coregulators, and components of signal transduction pathways. Thus, posttranslational modifications of many components of the basal and regulatory transcription machinery also play major roles in nuclear receptor-mediated transcriptional regulation. As for SXR, after binding to a variety of xenobiotics, it can activate the xenobiotic-response elements (XREs), which locate in the MDR1gene promoter, and stimulates transcription. P160family is involved in this process andcan bind directly to SXR. P160family functions as a scaffoldto recruit other coactivators. However, it still remainsunknownwhatelse factors are involved in activation and regulation of SXR/MDR1pathway.
Methylation of histones by protein arginine methyltransferases (PRMTs) is increasingly being acknowledged as an important aspect for the dynamic regulation of gene expression. The11mammalian PRMTs fall into two predominant classes, based on the types of methylarginine products they produce. Type Ⅰ enzymes (PRMT1, PRMT3, PRMT4/CARM1, PRMT6, and PRMT8) form monomethylarginine and asymmetric dimethylarginine, and type Ⅱ enzymes (PRMT5, PRMT7, and FBXO11) form monomethylarginine and symmetric dimethylarginine. PRMT4, namely coactivator-associated arginine methyltransferase1(CARM1) is initially identified as a SRC-2bindingprotein in a yeast two-hybrid screening. There are increasing evidences indicate CARM1plays pleiotropic roles in cell proliferation and survival.
Some researchers had investigated the expression of CARM1in many kinds of malignant tumors. Aberrant expression of CARM1has been linked to human breast cancer tissue in a few reports; however, current studies are contradictory and incomplete. The mRNA level of CARM1was found to be elevated in grade3breast tumors in a cohort of81human breast carcinomas of various types. While another study demonstrated there was inverse correlation between CARM1expression and tumor grade in ER+and LN-breast cancer cases. Kim YR et al reported CARM1overexpression was noted only in small number of breast cancer patients (27%). All these reports suggest CARM1is an important factor involved in progression and may affect prognostication of breast cancer. However, many of these studies were limited either by low n values of breast cancer patients or by a special tumor type. It still remains unclear whether CARM1expression is correlated with clinicopathological features, molecular subtype and prognosis.
CARM1functions as a coactivator for many nuclear receptors, such as the estrogen receptor (ER), androgen receptor (AR), the glucocorticoid receptor, and the thyroid receptor. However, it is still unknown whether CARM1is involved in the transcriptional regulation of MDR1. The regulation of SXR on MDR1requires the anticipation of p160protein family. While CARM1has been showed to be a coactivator of p160family, all members of p160family are natural substrates of CARM1. In summary, because CARM1activation plays an important role in the transcriptional regulation of nuclear receptor and p160, we presume that CARM1might be involved in the transcriptional activation of MDR1; probably through SXRpathway. It is necessary to investigate the correlation between CARM1, SXR and MDR1and the possible mechanism. This might contribute to understand the reversal of multidrug resistance and might provide new potential therapeutic targets.
In this study, we first examined expression of CARM1, ER, PR, HER2, p53, Ki-67index and MDR1in247cases of untreated primary invasive ductal carcinoma by immunohistochemistry. Furthermore, We detected the expression of CARM1in the breast cancer cell lines MCF-7and the multidrug resistant subline MCF-7/ADM. The results showed a higher expression of CARM1and MDR1/P-gp on both mRNA and protein levels in MCF-7/ADM cells, compared with the sensitive MCF-7cell lines.These results suggested the potential roles of CARM1in the development of multidrugresistance in breast cancer cells.Therefore, in this study, we proposed that the silencing of CARM1by plasmid-mediated expression of small interference RNA (siRNA) might result in the down-regulation of MDRl/P-gp, and thus reverse multidrug resistance in MDR cells. Anda full-length cDNA of CARM1mediated by plasmids was also transfected into MCF-7to investigate whetherexogenous overexpression of CARM1would improve drug resistance.
[Methods]
1. We examined the expression of CARM1, ER, PR, HER2, p53, Ki-67index and MDR1by immunohistochemistry of streptavidin peroxidase complex method. Then, we analyzed the relationship between CARM1, the clinical pathological characters, universal molecular markers and molecular subtypes respectively, as well as the correlation between CARM1and MDRl/P-gp.
2. Using RT-PCR and Western blot, we examined the expression of CARMl in breast cancer cell lines MCF-7and the multidrug resistant subline MCF-7/ADM.
3. Small hairpin siRNA sequences targeted at CARM1and negative controls, non-targeting siRNAs sequences, were designed and synthesized as64oligonucleotides. After annealed, they were cloned into the pSUPER. neo+GFP expression vector respectively. After comfirmed by enzyme digestion and DNA sequencing, the recombinant plasmids were amplified in bacteria and extracted subsequently.
4. The mammalian expression plasmid of pSG5.HA-CARM1was generously provided by Michael R. Stallcup (University of Southern California). We constructed pEGFP-C1-CARM1by insertion of CARM1which was cut out from pSG5.HA-CARM1with EcoRIinto pEGFP-C1plasmids. After comfirmed by enzyme digestion and DNA sequencing, the recombinant plasmids were amplified in bacteria and extracted subsequently.
5. The MDR cells ADM were transfected with pSUPER-siFZDl and pSUPER-siNotarget respectively. And sensitive cells MCF-7were transfected with pEGFP-C1-CARM1.After another48h culture, mRNA and protein expression of CARM1and MDRl/P-gp were examined by RT-PCR and Western blot. MTT assay was used to assess the effect of CARM1silencing and exogenous overexpression of CARM1on ADM and MCF-7cells respectively to doxorubicin.
[Results]
1. In invasive breast cancer tissues, CARM1expression was increased in invasive breast cancer cells compared with adjacent benign epithelium.The increased expression was observed in the cytoplasm and/or the nucleus Nuclear CARM1expression was associated with a younger age at diagnosis; multi-center origin or multiple tumors; a higher tumor grade; a higher rate of HER2, p53, and Ki-67expression; and a lower rate of ER and PR expression. We also found that the rate of CARM1expression was significantly different among different molecular subtypes of breast cancer. We showed that in the HER2subtype, the nuclear expression of CARM1was the highest (69.6%), followed by the luminal B (59.6%) and basal type (57.1%). The luminal A type showed the lowest percentage of cells with CARM1nuclear expression (41.3%). As to MDR1, the percentage of P-Gpexpressing was45.7%, and the expression of CARM1was positively related to that of P-gpexpression.
2. In MCF/ADM cells, CARM1was found to havehigher mRNA and protein levels in relation to MDRl/P-gp expression, compared with the sensitive cell line MCF-7.
3. The effects of CARM1interferencein ADM were verified by semi-quantitative RT-PCR. The level of CARM1and MDR1mRNA was down-regulated significantly in comparison with the control.Western blotanalysesindicated that CARM1and MDRl/P-gp were down-regulated in response to CARM1interference. MTT assay showed thatIC50value of doxorubicin wasdecreased remarkably after CARM1interferencein ADM cells.
4. The effects of CARM1exogenous overexpression in MCF-7cells were verified by semi-quantitative RT-PCR. The level of CARM1mRNA was up-regulated significantly in comparison with the control, while MDR1mRNA was notalterednotably.Western blotanalysesindicated that CARM1wasup-regulated afterexogenous overexpression of CARM1, whileMDR1/P-gp was not altered significantly. MTT assay also showed MCF-7IC50valueof doxorubicin did not changeremarkably in response to CARM1exogenous overexpression.
[Conclusions]
1. CARM1expression was increased in invasive breast cancer cells compared with adjacent benign epithelium. Nuclear CARM1expression was associated with a younger age at diagnosis; multi-center origin or multiple tumors; a higher tumor grade; a higher rate of HER2, p53, and Ki-67expression; and a lower rate of ER and PR expression. All of these predictors were clinicpathologic parameters that correlate with poor prognosis. We also found that the rate of CARM1expression was significantly different among different molecular subtypes of breast cancer.
2. In invasive breast cancer tissues, the expression of CARM1was positively related to that of MDR1. CARM1was also overexpressed in the multidrug resistant breast cancer cells, consistent with MDR1/P-gp expression.
3. In the multidrug resistant breast cancer cells, the silencing of CARM1decreased MDR1expression and reversed the multidrug resistance. It was indicated that CARM1was involved in the regulation of MDRl/P-gp.
4. The exogenous overexpressionofCARMl in breast cancer sensitive cells did not change MDR1/P-gp expression and function.These resultssupportedthe hypothesis that CARM1might be a secondary coactivator in SXR/MDR1pathway.
5. CARM1can modulate multidrug resistance through regulating the MDR1,probably through SXRpathway.CARM1is possible to be identified as a new molecular marker to predict multidrug resistance for personalized treatment and new latent target for MDR reversing in breast cancer cells.
引文
[I]Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008:GLOBOCAN 2008. Int J Cancer.2010.127(12):2893-917.
[2]Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol.2007.25(1):118-45.
[3]Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer:correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science.1987.235(4785):177-82.
[4]Ross JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM, Hortobagyi GN. The HER-2 receptor and breast cancer:ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist.2009. 14(4):320-68.
[5]Baselga J, Swain SM. Novel anticancer targets:revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer.2009.9(7):463-75.
[6]Wong ST, Goodin S. Overcoming drug resistance in patients with metastatic breast cancer. Pharmacotherapy.2009.29(8):954-65.
[7]Lee YH, Stallcup MR. Minireview:protein arginine methylation of nonhistone proteins in transcriptional regulation. Mol Endocrinol.2009.23(4):425-33.
[8]Bedford MT, Clarke SG. Protein arginine methylation in mammals:who, what, and why. Mol Cell.2009. 33(1):1-13.
[9]Chen D, Ma H, Hong H, et al. Regulation of transcription by a protein methyltransferase. Science.1999. 284(5423):2174-7.
[10]Ma H, Baumann CT, Li H, et al. Hormone-dependent, CARM1-directed, arginine-specific methylation of histone H3 on a steroid-regulated promoter. Curr Biol.2001.11 (24):1981-5.
[11]Daujat S, Bauer UM, Shah V, Turner B, Berger S, Kouzarides T. Crosstalk between CARM1 methylation and CBP acetylation on histone H3. Curr Biol.2002.12(24):2090-7.
[12]Ceschin DG, Walia M, Wenk SS, et al. Methylation specifies distinct estrogen-induced binding site repertoires of CBP to chromatin. Genes Dev.2011.25(11):1132-46.
[13]Ali S, Coombes RC. Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer.2002.2(2):101-12.
[14]El MS, Fabbrizio E, Rodriguez C, et al. Coactivator-associated arginine methyltransferase 1 (CARM1) is a positive regulator of the Cyclin El gene. Proc Natl Acad Sci U S A.2006.103(36):13351-6.
[15]Al-Dhaheri M, Wu J, Skliris GP, et al. CARM1 is an important determinant of ERalpha-dependent breast cancer cell differentiation and proliferation in breast cancer cells. Cancer Res.2011.71 (6):2118-28.
[16]Kim YR, Lee BK, Park RY, et al. Differential CARM1 expression in prostate and colorectal cancers. BMC Cancer.2010.10:197.
[17]Sunil R. Lakhani,Ian O. Ellis, Stuart J. Schnitt, Puay Hoon Tan, Marc J. van de Vijver. WHO Classification of Tumours of the Breast. Lyon:International Agency for Research on Cancer (IARC) Press; 2012
[18]Edge SB, Byrd DR, eds. AJCC Cancer Staging Manual.7th edition. New York:Springer; 2010
[19]Kim RG, Kim EK, Kim HA, et al. Prognostic significance of molecular subtype in T1N0M0 breast cancer: Korean experience. Eur J Surg Oncol.2011.37(7):629-34.
[20]Skliris GP, Leygue E, Curtis-Snell L, et al. Expression of oestrogen receptor-beta in oestrogen receptor-alpha negative human breast tumours. Br J CancerJAMA.2006.95(5):616-26.
[21]Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA.2006.295(21):2492-502.
[22]Kimura Y, Morita SY, Matsuo M, Ueda K. Mechanism of multidrug recognition by MDR1/ABCB1. Cancer Sci.2007.98(9):1303-10.
[23]Zhou SF. Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition. Xenobiotica.2008.38(7-8):802-32.
[24]Faneyte IF, Kristel PM, van de Vijver MJ. Determining MDR1/P-glycoprotein expression in breast cancer. Int J Cancer.2001.93(1):114-22.
[25]Takeshita A, Inagaki K, Igarashi-Migitaka J, Ozawa Y, Koibuchi N. MDR1-XRE The endocrine disrupting chemical, diethylhexyl phthalate, activates MDR1 gene expression in human colon cancer LS174T cells. J Endocrinol.2006.190(3):897-902.
[26]Geick A, Eichelbaum M, Burk O. Nuclear receptor response elements mediate induction of intestinal MDR1 by rifompin. J Biol Chem.2001.276(18):14581-7.
[27]Geick A, Eichelbaum M, Burk O.MDR1 Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem.2001.276(18):14581-7.
[28]Burk O, Arnold KA, Geick A, Tegude H, Eichelbaum M. A role for constitutive androstane receptor in the regulation of human intestinal MDR1 expression. Biol Chem.2005.386(6):503-13.
[29]Mani S, Huang H, Sundarababu S, et al. Activation of the steroid and xenobiotic receptor (human pregnane X receptor) by nontaxane microtubule-stabilizing agents. Clin Cancer Res.2005.11(17):6359-69.
[30]Kleiner HE, Xia X, Sonoda J, et al. Effects of naturally occurring coumarins on hepatic drug-metabolizing enzymes in mice. Toxicol Appl Pharmacol.2008.232(2):337-50.
[31]Frietze S, Lupien M, Silver PA, Brown M. CARM1 regulates estrogen-stimulated breast cancer growth through up-regulation of E2F1. Cancer Res.2008.68(1):301-6.
[32]Stallcup MR, Kim JH, Teyssier C, Lee YH, Ma H, Chen D. The roles of protein-protein interactions and protein methylation in transcriptional activation by nuclear receptors and their coactivators. J Steroid Biochem Mol Biol.2003.85(2-5):139-45.
[33]Su P, Zhang Q, Yang Q. Immunohistochemical analysis of Metadherin in proliferative and cancerous breast tissue. Diagn Pathol.2010.5:38.
[34]马超,周庚寅,肖颖,高鹏,郭玲玲,林晓燕HIF-la P-gp在腋淋巴结阴性乳腺癌组织中的表达及意义[J].中国肿瘤临床,2007,01：10-13.
[35]Collins LC, Marotti JD, Gelber S, Cole K, Ruddy K, Kereakoglow S, Brachtel EF, Schapira L, Come SE, Winer EP, Partridge AH:Pathologic features and molecular phenotype by patient age in a large cohort of young women with breast cancer. Breast Cancer Res Treat 2012,131:1061-1066
[36]Qin X, Peng Q, Qin A, et al. Association of COMT Val158Met polymorphism and breast cancer risk:an updated meta-analysis. Diagn Pathol.2012.7:136.
[37]Jones HA, Antonini N, Hart AA, et al. Impact of pathological characteristics on local relapse after breast-conserving therapy:a subgroup analysis of the EORTC boost versus no boost trial. J Clin Oncol. 2009.27(30):4939-47.
[38]van der Hage JA, Mieog JS, van de Velde CJ, Putter H, Bartelink H, van de Vijver MJ. Impact of established prognostic factors and molecular subtype in very young breast cancer patients:pooled analysis of four EORTC randomized controlled trials. Breast Cancer Res.2011.13(3):R68.
[39]Collins LC, Marotti JD, Gelber S, et al. Pathologic features and molecular phenotype by patient age in a large cohort of young women with breast cancer. Breast Cancer Res Treat.2012.131(3):1061-6.
[40]Wu Q, Bruce AW, Jedrusik A, et al. CARM1 is required in embryonic stem cells to maintain pluripotency and resist differentiation. Stem Cells.2009.27(11):2637-45.
[41]Feng Q, He B, Jung SY, et al. Biochemical control of CARM1 enzymatic activity by phosphorylation. J Biol Chem.2009.284(52):36167-74.
[42]Urwyler O, Zhang L, Li X, Imboden H, Suter B. Tissue-dependent subcellular localization of Drosophila arginine methyl-transferase 4 (DART4), a coactivator whose overexpression affects neither viability nor differentiation. Differentiation.2007.75(8):757-65.
[43]Yadav N, Lee J, Kim J, et al. Specific protein methylation defects and gene expression perturbations in coactivator-associated arginine methyltransferase 1-deficient mice. Proc Natl Acad Sci U S A.2003. 100(11):6464-8.
[44]Lupien M, Eeckhoute J, Meyer CA, et al. Coactivator function defines the active estrogen receptor alpha cistrome. Mol Cell Biol.2009.29(12):3413-23.
[45]Frietze S, Lupien M, Silver PA, Brown M. CARM1 regulates estrogen-stimulated breast cancer growth through up-regulation of E2F1. Cancer Res.2008.68(1):301-6.
[46]Chen D, Ma H, Hong H, et al. Regulation of transcription by a protein methyltransferase. Science.1999. 284(5423):2174-7.
[47]Carascossa S, Dudek P, Cenni B, Briand PA, Picard D. CARM1 mediates the ligand-independent and tamoxifen-resistant activation of the estrogen receptor alpha by cAMP. Genes Dev.2010.24(7):708-19.
[48]Kaufman B, Mackey JR, Clemens MR, et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer:results from the randomized phase Ⅲ TAnDEM study. J Clin Oncol.2009.27(33):5529-37.
[49]Higgins MJ, Baselga J. Targeted therapies for breast cancer. J Clin Invest.2011.121(10):3797-803.
[50]Feng Q, Yi P, Wong J, O'Malley BW. Signaling within a coactivator complex:methylation of SRC-3/AIB1 is a molecular switch for complex disassembly. Mol Cell Biol.2006.26(21):7846-57.
[51]Lahusen T, Henke RT, Kagan BL, Wellstein A, Riegel AT. The role and regulation of the nuclear receptor co-activator AIB1 in breast cancer. Breast Cancer Res Treat.2009.116(2):225-37.
[52]Kim D, Lee J, Cheng D, et al. Enzymatic activity is required for the in vivo functions of CARM1. J Biol Chem.2010.285(2):1147-52.
[53]Selvi BR, Batta K, Kishore AH, et al. Identification of a novel inhibitor of coactivator-associated arginine methyltransferase 1 (CARM1)-mediated methylation of histone H3 Arg-17. J Biol Chem.2010.285(10): 7143-52.
[54]Huynh T, Chen Z, Pang S, et al. Optimization of pyrazole inhibitors of Coactivator Associated Arginine Methyltransferase 1 (CARM1). Bioorg Med Chem Lett.2009.19(11):2924-7.
[55]Purandare AV, Chen Z, Huynh T, et al. Pyrazole inhibitors of coactivator associated arginine methyltransferase 1 (CARM1). Bioorg Med Chem Lett.2008.18(15):4438-41.
[1]Kwong A, Mang OW, Wong CH, Chau WW, Law SC. Breast Cancer in Hong Kong, Southern China:The First Population-Based Analysis of Epidemiological Characteristics, Stage-Specific, Cancer-Specific, and Disease-Free Survival in Breast Cancer Patients:1997-2001. Ann Surg Oncol.2011.
[2]Parkin DM, Fernandez LM. Use of statistics to assess the global burden of breast cancer. Breast J.2006.12 Suppl 1:S70-80.
[3]Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM:GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide:IARC CancerBase No.10. Lyon, France:International Agency for Research on Cancer 2010.
[4]Kimura Y, Morita SY, Matsuo M, Ueda K. Mechanism of multidrug recognition by MDR1/ABCB1. Cancer Sci.2007.98(9):1303-10.
[5]Panczyk M, Salagacka A, Mirowski M. [MDR1 (ABCB1) gene encoding glycoprotein P (P-gp), a member of ABC transporter superfamily:consequences for therapy and progression of neoplastic diseases]. Postepy Biochem.2007.53(4):361-73.
[6]Leonessa F, Clarke R. ATP binding cassette transporters and drug resistance in breast cancer. Endocr Relat Cancer.2003.10(1):43-73.
[7]Zhou SF. Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition. Xenobiotica.2008.38(7-8):802-32.
[8]Takeshita A, Inagaki K, Igarashi-Migitaka J, Ozawa Y, Koibuchi N. MDR1-XRE The endocrine disrupting chemical, diethylhexyl phthalate, activates MDR1 gene expression in human colon cancer LS174T cells. J Endocrinol.2006.190(3):897-902.
[9]Geick A, Eichelbaum M, Burk O. Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem.2001.276(18):14581-7.
[10]Geick A, Eichelbaum M, Burk O. MDR1 Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem.2001.276(18):14581-7.
[11]Burk O, Arnold KA, Geick A, Tegude H, Eichelbaum M. A role for constitutive androstane receptor in the regulation of human intestinal MDR1 expression. Biol Chem.2005.386(6):503-13.
[12]Mani S, Huang H, Sundarababu S, et al. Activation of the steroid and xenobiotic receptor (human pregnane X receptor) by nontaxane microtubule-stabilizing agents. Clin Cancer Res.2005.11(17):6359-69.
[13]Kleiner HE, Xia X, Sonoda J, et al. Effects of naturally occurring coumarins on hepatic drug-metabolizing enzymes in mice. Toxicol Appl Pharmacol.2008.232(2):337-50.
[14]Frietze S, Lupien M, Silver PA, Brown M详细阅读CARM1 regulates estrogen-stimulated breast cancer growth through up-regulation of E2F1. Cancer Res.2008.68(1):301-6.
[15]Bedford MT, Clarke SG. Protein arginine methylation in mammals:who, what, and why. Mol Cell.2009. 33(1):1-13.
[16]Ma H, Baumann CT, Li H, et al. Hormone-dependent, CARM1-directed, arginine-specific methylation of histone H3 on a steroid-regulated promoter. Curr Biol.2001.11(24):1981-5.
[17]Naeem H, Cheng D, Zhao Q, et al. The activity and stability of the transcriptional coactivator p/CIP/SRC-3 are regulated by CARM1-dependent methylation. Mol Cell Biol.2007.27(1):120-34.
[18]Kim D, Lee J, Cheng D, et al. Enzymatic activity is required for the in vivo functions of CARM1. J Biol Chem.2010.285(2):1147-52.
[19]Wysocka J, Allis CD, Coonrod S. Histone arginine methylation and its dynamic regulation. Front Biosci. 2006.11:344-55.
[20]El MS, Fabbrizio E, Rodriguez C, et al. Coactivator-associated arginine methyltransferase 1 (CARM1) is a positive regulator of the Cyclin E1 gene. Proc Natl Acad Sci USA.2006.103(36):13351-6.
[21]El MS, Fabbrizio E, Rodriguez C, et al. Coactivator-associated arginine methyltransferase 1 (CARM1) is a positive regulator of the Cyclin E1 gene. Proc Natl Acad Sci U S A.2006.103(36):13351-6.
[22]Zhang H, Zhang X, Wu X, et al. Interference of Frizzled 1 (FZD1) reverses multidrug resistance in breast cancer cells through the Wnt/beta-catenin pathway. Cancer Lett.2012.323(1):106-13.
[23]Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta.1976.455(1):152-62.
[24]Chen CJ, Chin JE, Ueda K, et al. Internal duplication and homology with bacterial transport proteins in the mdrl (P-glycoprotein) gene from multidrug-resistant human cells. Cell.1986.47(3):381-9.
[25]Zhou SF. Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition. Xenobiotica.2008.38(7-8):802-32.
[26]Chen T. Overcoming drug resistance by regulating nuclear receptors. Adv Drug Deliv Rev.2010.62(13): 1257-64.
[27]Lee CH. Reversing agents for ATP-binding cassette drug transporters. Methods Mol Biol.2010.596: 325-40.
[28]Chan GN, Bendayan R. BBBMolecular and functional characterization of P-glycoprotein in vitro. Methods Mol Biol.2011.686:313-36.
[29]Zhou C, Verma S, Blumberg B. The steroid and xenobiotic receptor (SXR), beyond xenobiotic metabolism. Nucl Recept Signal.2009.7:e001.
[30]Takeshita A, Koibuchi N, Oka J, Taguchi M, Shishiba Y, Ozawa Y. Bisphenol-A, an environmental estrogen, activates the human orphan nuclear receptor, steroid and xenobiotic receptor-mediated transcription. Eur J Endocrinol.2001.145(4):513-7.
[31]Feng Q, He B, Jung SY, et al. Biochemical control of CARM1 enzymatic activity by phosphorylation. J Biol Chem.2009.284(52):36167-74.
[32]Troffer-Charlier N, Cura V, Hassenboehler P, Moras D, Cavarelli J. Functional insights from structures of coactivator-associated arginine methyltransferase 1 domains. EMBO J.2007.26(20):4391-401.
[33]Lee YH, Stallcup MR. Minireview:protein arginine methylation of nonhistone proteins in transcriptional regulation. Mol Endocrinol.2009.23(4):425-33.
[34]Litt M, Qiu Y, Huang S. Histone arginine methylations:their roles in chromatin dynamics and transcriptional regulation. Biosci Rep.2009.29(2):131-41.
[35]Yue WW, Hassler M, Roe SM, Thompson-Vale V, Pearl LH. Insights into histone code syntax from structural and biochemical studies of CARM1 methyltransferase. EMBO J.2007.26(20):4402-12.
[36]Chen D, Ma H, Hong H, et al. Regulation of transcription by a protein methyltransferase. Science.1999. 284(5423):2174-7.
[37]Stallcup MR, Chen D, Koh SS, et al. Co-operation between protein-acetylating and protein-methylating co-activators in transcriptional activation. Biochem Soc Trans.2000.28(4):415-8.
[38]Yadav N, Lee J, Kim J, et al. Specific protein methylation defects and gene expression perturbations in coactivator-associated arginine methyltransferase 1-deficient mice. Proc Natl Acad Sci USA.2003. 100(11):6464-8.
[39]Torres-Padilla ME, Parfitt DE, Kouzarides T, Zernicka-Goetz M. Histone arginine methylation regulates pluripotency in the early mouse embryo. Nature.2007.445(7124):214-8.
[40]Chevillard-Briet M, Trouche D, Vandel L. Control of CBP co-activating activity by arginine methylation. EMBO J.2002.21(20):5457-66.
[41]Lupien M, Eeckhoute J, Meyer CA, et al. Coactivator function defines the active estrogen receptor alpha cistrome. Mol Cell Biol.2009.29(12):3413-23.
[42]Li H, Park S, Kilburn B, et al. Lipopolysaccharide-induced methylation of HuR, an mRNA-stabilizing protein, by CARM1. Coactivator-associated arginine methyltransferase. J Biol Chem.2002.277(47): 44623-30.
[43]Higashimoto K, Kuhn P, Desai D, Cheng X, Xu W. Phosphorylation-mediated inactivation of coactivator-associated arginine methyltransferase 1. Proc Natl Acad Sci U S A.2007.104(30):12318-23.
[44]Hong H, Kao C, Jeng MH, et al. Aberrant expression of CARM1, a transcriptional coactivator of androgen receptor, in the development of prostate carcinoma and androgen-independent status. Cancer.2004.101(1): 83-9.
[45]Majumder S, Liu Y, Ford OH 3rd, Mohler JL, Whang YE. Involvement of arginine methyltransferase CARM1 in androgen receptor function and prostate cancer cell viability. Prostate.2006.66(12):1292-301.
[46]Ou CY, Labonte MJ, Manegold PC, et al. A coactivator role of CARM1 in the dysregulation of {beta}-catenin activity in colorectal cancer cell growth and gene expression. Mol Cancer Res.2011.
[47]Cheng H, Qin Y, Fan H, et al. Overexpression of CARM1 in breast cancer is correlated with poorly characterized clinicopathologic parameters and molecular subtypes. Diagn Pathol.2013.8(1):129.
[1]Kimura Y, Morita SY, Matsuo M, Ueda K. Mechanism of multidrug recognition by MDR1/ABCB1. Cancer Sci.2007.98(9):1303-10.
[2]Chen T. Overcoming drug resistance by regulating nuclear receptors. Adv Drug Deliv Rev.2010.62(13): 1257-64.
[3]Lee CH. Reversing agents for ATP-binding cassette drug transporters. Methods Mol Biol.2010.596: 325-40.
[4]Takeshita A, Inagaki K, Igarashi-Migitaka J, Ozawa Y, Koibuchi N. MDR1-XRE The endocrine disrupting chemical, diethylhexyl phthalate, activates MDR1 gene expression in human colon cancer LS174T cells. J Endocrinol.2006.190(3):897-902.
[5]Geick A, Eichelbaum M, Burk O. Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem.2001.276(18):14581-7.
[6]Geick A, Eichelbaum M, Burk O. MDR1 Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem.2001.276(18):14581-7.
[7]Stallcup MR, Kim JH, Teyssier C, Lee YH, Ma H, Chen D. The roles of protein-protein interactions and protein methylation in transcriptional activation by nuclear receptors and their coactivators. J Steroid Biochem Mol Biol.2003.85(2-5):139-45.
[8]Wysocka J, Allis CD, Coonrod S. Histone arginine methylation and its dynamic regulation. Front Biosci. 2006.11:344-55.
[9]Lee YH, Stallcup MR. Minireview:protein arginine methylation of nonhistone proteins in transcriptional regulation. Mol Endocrinol.2009.23(4):425-33.
[10]Burk O, Arnold KA, Geick A, Tegude H, Eichelbaum M. A role for constitutive androstane receptor in the regulation of human intestinal MDR1 expression. Biol Chem.2005.386(6):503-13.
[11]Mani S, Huang H, Sundarababu S, et al. Activation of the steroid and xenobiotic receptor (human pregnane X receptor) by nontaxane microtubule-stabilizing agents. Clin Cancer Res.2005.11(17):6359-69.
[12]Kleiner HE, Xia X, Sonoda J, et al. Effects of naturally occurring coumarins on hepatic drug-metabolizing enzymes in mice. Toxicol Appl Pharmacol.2008.232(2):337-50.
[13]Chen D, Ma H, Hong H, et al. Regulation of transcription by a protein methyltransferase. Science.1999. 284(5423):2174-7.
[14]Naeem H, Cheng D, Zhao Q, et al. The activity and stability of the transcriptional coactivator p/CIP/SRC-3 are regulated by CARM1-dependent methylation. Mol Cell Biol.2007.27(1):120-34.
[15]Frietze S, Lupien M, Silver PA, Brown M. CARM1 regulates estrogen-stimulated breast cancer growth through up-regulation of E2F1. Cancer Res.2008.68(1):301-6.
[16]El MS, Fabbrizio E, Rodriguez C, et al. Coactivator-associated arginine methyltransferase 1 (CARM1) is a positive regulator of the Cyclin El gene. Proc Natl Acad Sci U S A.2006.103(36):13351-6.
[17]Cheng H, Qin Y, Fan H, et al. Overexpression of CARM1 in breast cancer is correlated with poorly characterized clinicopathologic parameters and molecular subtypes. Diagn Pathol.2013.8(1):129.
[18]Zhang H, Zhang X, Wu X, et al. Interference of Frizzled 1 (CARM1) reverses multidrug resistance in breast cancer cells through the Wnt/beta-catenin pathway. Cancer Lett.2012.323(1):106-13.
[19]Majumder S, Liu Y, Ford OH 3rd, Mohler JL, Whang YE. Involvement of arginine methyltransferase CARM1 in androgen receptor function and prostate cancer cell viability. Prostate.2006.66(12):1292-301.
[20]Barr FD, Krohmer LJ, Hamilton JW, Sheldon LA. Disruption of histone modification and CARM1 recruitment by arsenic represses transcription at glucocorticoid receptor-regulated promoters. PLOS ONE. 2009.4(8):e6766.
[21]Wang H, LeCluyse EL. Role of orphan nuclear receptors in the regulation of drug-metabolising enzymes. Clin Pharmacokinet.2003.42(15):1331-57.
[22]Glass CK, Rosenfeld MG. The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev.2000.14(2):121-41.
[23]Belandia B, Orford RL, Hurst HC, Parker MG. Targeting of SWI/SNF chromatin remodelling complexes to estrogen-responsive genes. EMBO J.2002.21(15):4094-103.
[24]Stallcup MR, Kim JH, Teyssier C, Lee YH, Ma H, Chen D. The roles of protein-protein interactions and protein methylation in transcriptional activation by nuclear receptors and their coactivators. J Steroid Biochem Mol Biol.2003.85(2-5):139-45.
[25]Kawana K, Ikuta T, Kobayashi Y, Gotoh O, Takeda K, Kawajiri K. Molecular mechanism of nuclear translocation of an orphan nuclear receptor, SXR. Mol Pharmacol.2003.63(3):524-31.
[26]Zhou C, Verma S, Blumberg B. The steroid and xenobiotic receptor (SXR), beyond xenobiotic metabolism. Nucl Recept Signal.2009.7:e001.
[27]Synold TW, Dussault I, Forman BM. The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat Med.2001.7(5):584-90.
[28]Basseville A, Preisser L, de Carne Trecesson S, et al.3.778 Irinotecan induces steroid and xenobiotic receptor (SXR) signaling to detoxification pathway in colon cancer cells. Mol Cancer.2011.10:80.
[29]Sonoda J, Pei L, Evans RM. Nuclear receptors:decoding metabolic disease. FEBS Lett.2008.582(1):2-9.
[30]Blumberg B, Sabbagh W Jr, Juguilon H, et al. SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev.1998.12(20):3195-205.
[31]Kimchi-Sarfaty C, Oh JM, Kim IW, et al. A "silent" polymorphism in the MDR1 gene changes substrate specificity. Science.2007.315(5811):525-8.
[32]Kleiner HE, Xia X, Sonoda J, et al. Effects of naturally occurring coumarins on hepatic drug-metabolizing enzymes in mice. Toxicol Appl Pharmacol.2008.232(2):337-50.
[33]Takeshita A, Taguchi M, Koibuchi N, Ozawa Y. Putative role of the orphan nuclear receptor SXR (steroid and xenobiotic receptor) in the mechanism of CYP3A4 inhibition by xenobiotics. J Biol Chem.2002. 277(36):32453-8.
[34]Kim JH, Li H, Stallcup MR. CoCoA, a nuclear receptor coactivator which acts through an N-terminal activation domain of p160 coactivators. Mol Cell.2003.12(6):1537-49.
[35]Chen D, Huang SM, Stallcup MR. Synergistic, p160 coactivator-dependent enhancement of estrogen receptor function by CARM1 and p300. J Biol Chem.2000.275(52):40810-6.
[36]Koh SS, Li H, Lee YH, Widelitz RB, Chuong CM, Stallcup MR. Synergistic coactivator function by coactivator-associated arginine methyltransferase (CARM) 1 and beta-catenin with two different classes of DNA-binding transcriptional activators. J Biol Chem.2002.277(29):26031-5.
[37]Fauquier L, Duboe C, Jore C, Trouche D, Vandel L. Dual role of the arginine methyltransferase CARM 1 in the regulation of c-Fos target genes. FASEB J.2008.22(9):3337-47.
[2]Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol.2007.25(1):118-45.
[3]Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer:correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science.1987.235(4785):177-82.
[4]Ross JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM, Hortobagyi GN. The HER-2 receptor and breast cancer:ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist.2009. 14(4):320-68.
[5]Baselga J, Swain SM. Novel anticancer targets:revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer.2009.9(7):463-75.
[6]Wong ST, Goodin S. Overcoming drug resistance in patients with metastatic breast cancer. Pharmacotherapy.2009.29(8):954-65.
[7]Lee YH, Stallcup MR. Minireview:protein arginine methylation of nonhistone proteins in transcriptional regulation. Mol Endocrinol.2009.23(4):425-33.
[8]Bedford MT, Clarke SG. Protein arginine methylation in mammals:who, what, and why. Mol Cell.2009. 33(1):1-13.
[9]Chen D, Ma H, Hong H, et al. Regulation of transcription by a protein methyltransferase. Science.1999. 284(5423):2174-7.
[10]Ma H, Baumann CT, Li H, et al. Hormone-dependent, CARM1-directed, arginine-specific methylation of histone H3 on a steroid-regulated promoter. Curr Biol.2001.11 (24):1981-5.
[11]Daujat S, Bauer UM, Shah V, Turner B, Berger S, Kouzarides T. Crosstalk between CARM1 methylation and CBP acetylation on histone H3. Curr Biol.2002.12(24):2090-7.
[12]Ceschin DG, Walia M, Wenk SS, et al. Methylation specifies distinct estrogen-induced binding site repertoires of CBP to chromatin. Genes Dev.2011.25(11):1132-46.
[13]Ali S, Coombes RC. Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer.2002.2(2):101-12.
[14]El MS, Fabbrizio E, Rodriguez C, et al. Coactivator-associated arginine methyltransferase 1 (CARM1) is a positive regulator of the Cyclin El gene. Proc Natl Acad Sci U S A.2006.103(36):13351-6.
[15]Al-Dhaheri M, Wu J, Skliris GP, et al. CARM1 is an important determinant of ERalpha-dependent breast cancer cell differentiation and proliferation in breast cancer cells. Cancer Res.2011.71 (6):2118-28.
[16]Kim YR, Lee BK, Park RY, et al. Differential CARM1 expression in prostate and colorectal cancers. BMC Cancer.2010.10:197.
[17]Sunil R. Lakhani,Ian O. Ellis, Stuart J. Schnitt, Puay Hoon Tan, Marc J. van de Vijver. WHO Classification of Tumours of the Breast. Lyon:International Agency for Research on Cancer (IARC) Press; 2012
[18]Edge SB, Byrd DR, eds. AJCC Cancer Staging Manual.7th edition. New York:Springer; 2010
[19]Kim RG, Kim EK, Kim HA, et al. Prognostic significance of molecular subtype in T1N0M0 breast cancer: Korean experience. Eur J Surg Oncol.2011.37(7):629-34.
[20]Skliris GP, Leygue E, Curtis-Snell L, et al. Expression of oestrogen receptor-beta in oestrogen receptor-alpha negative human breast tumours. Br J CancerJAMA.2006.95(5):616-26.
[21]Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA.2006.295(21):2492-502.
[22]Kimura Y, Morita SY, Matsuo M, Ueda K. Mechanism of multidrug recognition by MDR1/ABCB1. Cancer Sci.2007.98(9):1303-10.
[23]Zhou SF. Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition. Xenobiotica.2008.38(7-8):802-32.
[24]Faneyte IF, Kristel PM, van de Vijver MJ. Determining MDR1/P-glycoprotein expression in breast cancer. Int J Cancer.2001.93(1):114-22.
[25]Takeshita A, Inagaki K, Igarashi-Migitaka J, Ozawa Y, Koibuchi N. MDR1-XRE The endocrine disrupting chemical, diethylhexyl phthalate, activates MDR1 gene expression in human colon cancer LS174T cells. J Endocrinol.2006.190(3):897-902.
[26]Geick A, Eichelbaum M, Burk O. Nuclear receptor response elements mediate induction of intestinal MDR1 by rifompin. J Biol Chem.2001.276(18):14581-7.
[27]Geick A, Eichelbaum M, Burk O.MDR1 Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem.2001.276(18):14581-7.
[28]Burk O, Arnold KA, Geick A, Tegude H, Eichelbaum M. A role for constitutive androstane receptor in the regulation of human intestinal MDR1 expression. Biol Chem.2005.386(6):503-13.
[29]Mani S, Huang H, Sundarababu S, et al. Activation of the steroid and xenobiotic receptor (human pregnane X receptor) by nontaxane microtubule-stabilizing agents. Clin Cancer Res.2005.11(17):6359-69.
[30]Kleiner HE, Xia X, Sonoda J, et al. Effects of naturally occurring coumarins on hepatic drug-metabolizing enzymes in mice. Toxicol Appl Pharmacol.2008.232(2):337-50.
[31]Frietze S, Lupien M, Silver PA, Brown M. CARM1 regulates estrogen-stimulated breast cancer growth through up-regulation of E2F1. Cancer Res.2008.68(1):301-6.
[32]Stallcup MR, Kim JH, Teyssier C, Lee YH, Ma H, Chen D. The roles of protein-protein interactions and protein methylation in transcriptional activation by nuclear receptors and their coactivators. J Steroid Biochem Mol Biol.2003.85(2-5):139-45.
[33]Su P, Zhang Q, Yang Q. Immunohistochemical analysis of Metadherin in proliferative and cancerous breast tissue. Diagn Pathol.2010.5:38.
[34]马超,周庚寅,肖颖,高鹏,郭玲玲,林晓燕HIF-la P-gp在腋淋巴结阴性乳腺癌组织中的表达及意义[J].中国肿瘤临床,2007,01：10-13.
[35]Collins LC, Marotti JD, Gelber S, Cole K, Ruddy K, Kereakoglow S, Brachtel EF, Schapira L, Come SE, Winer EP, Partridge AH:Pathologic features and molecular phenotype by patient age in a large cohort of young women with breast cancer. Breast Cancer Res Treat 2012,131:1061-1066
[36]Qin X, Peng Q, Qin A, et al. Association of COMT Val158Met polymorphism and breast cancer risk:an updated meta-analysis. Diagn Pathol.2012.7:136.
[37]Jones HA, Antonini N, Hart AA, et al. Impact of pathological characteristics on local relapse after breast-conserving therapy:a subgroup analysis of the EORTC boost versus no boost trial. J Clin Oncol. 2009.27(30):4939-47.
[38]van der Hage JA, Mieog JS, van de Velde CJ, Putter H, Bartelink H, van de Vijver MJ. Impact of established prognostic factors and molecular subtype in very young breast cancer patients:pooled analysis of four EORTC randomized controlled trials. Breast Cancer Res.2011.13(3):R68.
[39]Collins LC, Marotti JD, Gelber S, et al. Pathologic features and molecular phenotype by patient age in a large cohort of young women with breast cancer. Breast Cancer Res Treat.2012.131(3):1061-6.
[40]Wu Q, Bruce AW, Jedrusik A, et al. CARM1 is required in embryonic stem cells to maintain pluripotency and resist differentiation. Stem Cells.2009.27(11):2637-45.
[41]Feng Q, He B, Jung SY, et al. Biochemical control of CARM1 enzymatic activity by phosphorylation. J Biol Chem.2009.284(52):36167-74.
[42]Urwyler O, Zhang L, Li X, Imboden H, Suter B. Tissue-dependent subcellular localization of Drosophila arginine methyl-transferase 4 (DART4), a coactivator whose overexpression affects neither viability nor differentiation. Differentiation.2007.75(8):757-65.
[43]Yadav N, Lee J, Kim J, et al. Specific protein methylation defects and gene expression perturbations in coactivator-associated arginine methyltransferase 1-deficient mice. Proc Natl Acad Sci U S A.2003. 100(11):6464-8.
[44]Lupien M, Eeckhoute J, Meyer CA, et al. Coactivator function defines the active estrogen receptor alpha cistrome. Mol Cell Biol.2009.29(12):3413-23.
[45]Frietze S, Lupien M, Silver PA, Brown M. CARM1 regulates estrogen-stimulated breast cancer growth through up-regulation of E2F1. Cancer Res.2008.68(1):301-6.
[46]Chen D, Ma H, Hong H, et al. Regulation of transcription by a protein methyltransferase. Science.1999. 284(5423):2174-7.
[47]Carascossa S, Dudek P, Cenni B, Briand PA, Picard D. CARM1 mediates the ligand-independent and tamoxifen-resistant activation of the estrogen receptor alpha by cAMP. Genes Dev.2010.24(7):708-19.
[48]Kaufman B, Mackey JR, Clemens MR, et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer:results from the randomized phase Ⅲ TAnDEM study. J Clin Oncol.2009.27(33):5529-37.
[49]Higgins MJ, Baselga J. Targeted therapies for breast cancer. J Clin Invest.2011.121(10):3797-803.
[50]Feng Q, Yi P, Wong J, O'Malley BW. Signaling within a coactivator complex:methylation of SRC-3/AIB1 is a molecular switch for complex disassembly. Mol Cell Biol.2006.26(21):7846-57.
[51]Lahusen T, Henke RT, Kagan BL, Wellstein A, Riegel AT. The role and regulation of the nuclear receptor co-activator AIB1 in breast cancer. Breast Cancer Res Treat.2009.116(2):225-37.
[52]Kim D, Lee J, Cheng D, et al. Enzymatic activity is required for the in vivo functions of CARM1. J Biol Chem.2010.285(2):1147-52.
[53]Selvi BR, Batta K, Kishore AH, et al. Identification of a novel inhibitor of coactivator-associated arginine methyltransferase 1 (CARM1)-mediated methylation of histone H3 Arg-17. J Biol Chem.2010.285(10): 7143-52.
[54]Huynh T, Chen Z, Pang S, et al. Optimization of pyrazole inhibitors of Coactivator Associated Arginine Methyltransferase 1 (CARM1). Bioorg Med Chem Lett.2009.19(11):2924-7.
[55]Purandare AV, Chen Z, Huynh T, et al. Pyrazole inhibitors of coactivator associated arginine methyltransferase 1 (CARM1). Bioorg Med Chem Lett.2008.18(15):4438-41.
[1]Kwong A, Mang OW, Wong CH, Chau WW, Law SC. Breast Cancer in Hong Kong, Southern China:The First Population-Based Analysis of Epidemiological Characteristics, Stage-Specific, Cancer-Specific, and Disease-Free Survival in Breast Cancer Patients:1997-2001. Ann Surg Oncol.2011.
[2]Parkin DM, Fernandez LM. Use of statistics to assess the global burden of breast cancer. Breast J.2006.12 Suppl 1:S70-80.
[3]Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM:GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide:IARC CancerBase No.10. Lyon, France:International Agency for Research on Cancer 2010.
[4]Kimura Y, Morita SY, Matsuo M, Ueda K. Mechanism of multidrug recognition by MDR1/ABCB1. Cancer Sci.2007.98(9):1303-10.
[5]Panczyk M, Salagacka A, Mirowski M. [MDR1 (ABCB1) gene encoding glycoprotein P (P-gp), a member of ABC transporter superfamily:consequences for therapy and progression of neoplastic diseases]. Postepy Biochem.2007.53(4):361-73.
[6]Leonessa F, Clarke R. ATP binding cassette transporters and drug resistance in breast cancer. Endocr Relat Cancer.2003.10(1):43-73.
[7]Zhou SF. Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition. Xenobiotica.2008.38(7-8):802-32.
[8]Takeshita A, Inagaki K, Igarashi-Migitaka J, Ozawa Y, Koibuchi N. MDR1-XRE The endocrine disrupting chemical, diethylhexyl phthalate, activates MDR1 gene expression in human colon cancer LS174T cells. J Endocrinol.2006.190(3):897-902.
[9]Geick A, Eichelbaum M, Burk O. Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem.2001.276(18):14581-7.
[10]Geick A, Eichelbaum M, Burk O. MDR1 Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem.2001.276(18):14581-7.
[11]Burk O, Arnold KA, Geick A, Tegude H, Eichelbaum M. A role for constitutive androstane receptor in the regulation of human intestinal MDR1 expression. Biol Chem.2005.386(6):503-13.
[12]Mani S, Huang H, Sundarababu S, et al. Activation of the steroid and xenobiotic receptor (human pregnane X receptor) by nontaxane microtubule-stabilizing agents. Clin Cancer Res.2005.11(17):6359-69.
[13]Kleiner HE, Xia X, Sonoda J, et al. Effects of naturally occurring coumarins on hepatic drug-metabolizing enzymes in mice. Toxicol Appl Pharmacol.2008.232(2):337-50.
[14]Frietze S, Lupien M, Silver PA, Brown M详细阅读CARM1 regulates estrogen-stimulated breast cancer growth through up-regulation of E2F1. Cancer Res.2008.68(1):301-6.
[15]Bedford MT, Clarke SG. Protein arginine methylation in mammals:who, what, and why. Mol Cell.2009. 33(1):1-13.
[16]Ma H, Baumann CT, Li H, et al. Hormone-dependent, CARM1-directed, arginine-specific methylation of histone H3 on a steroid-regulated promoter. Curr Biol.2001.11(24):1981-5.
[17]Naeem H, Cheng D, Zhao Q, et al. The activity and stability of the transcriptional coactivator p/CIP/SRC-3 are regulated by CARM1-dependent methylation. Mol Cell Biol.2007.27(1):120-34.
[18]Kim D, Lee J, Cheng D, et al. Enzymatic activity is required for the in vivo functions of CARM1. J Biol Chem.2010.285(2):1147-52.
[19]Wysocka J, Allis CD, Coonrod S. Histone arginine methylation and its dynamic regulation. Front Biosci. 2006.11:344-55.
[20]El MS, Fabbrizio E, Rodriguez C, et al. Coactivator-associated arginine methyltransferase 1 (CARM1) is a positive regulator of the Cyclin E1 gene. Proc Natl Acad Sci USA.2006.103(36):13351-6.
[21]El MS, Fabbrizio E, Rodriguez C, et al. Coactivator-associated arginine methyltransferase 1 (CARM1) is a positive regulator of the Cyclin E1 gene. Proc Natl Acad Sci U S A.2006.103(36):13351-6.
[22]Zhang H, Zhang X, Wu X, et al. Interference of Frizzled 1 (FZD1) reverses multidrug resistance in breast cancer cells through the Wnt/beta-catenin pathway. Cancer Lett.2012.323(1):106-13.
[23]Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta.1976.455(1):152-62.
[24]Chen CJ, Chin JE, Ueda K, et al. Internal duplication and homology with bacterial transport proteins in the mdrl (P-glycoprotein) gene from multidrug-resistant human cells. Cell.1986.47(3):381-9.
[25]Zhou SF. Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition. Xenobiotica.2008.38(7-8):802-32.
[26]Chen T. Overcoming drug resistance by regulating nuclear receptors. Adv Drug Deliv Rev.2010.62(13): 1257-64.
[27]Lee CH. Reversing agents for ATP-binding cassette drug transporters. Methods Mol Biol.2010.596: 325-40.
[28]Chan GN, Bendayan R. BBBMolecular and functional characterization of P-glycoprotein in vitro. Methods Mol Biol.2011.686:313-36.
[29]Zhou C, Verma S, Blumberg B. The steroid and xenobiotic receptor (SXR), beyond xenobiotic metabolism. Nucl Recept Signal.2009.7:e001.
[30]Takeshita A, Koibuchi N, Oka J, Taguchi M, Shishiba Y, Ozawa Y. Bisphenol-A, an environmental estrogen, activates the human orphan nuclear receptor, steroid and xenobiotic receptor-mediated transcription. Eur J Endocrinol.2001.145(4):513-7.
[31]Feng Q, He B, Jung SY, et al. Biochemical control of CARM1 enzymatic activity by phosphorylation. J Biol Chem.2009.284(52):36167-74.
[32]Troffer-Charlier N, Cura V, Hassenboehler P, Moras D, Cavarelli J. Functional insights from structures of coactivator-associated arginine methyltransferase 1 domains. EMBO J.2007.26(20):4391-401.
[33]Lee YH, Stallcup MR. Minireview:protein arginine methylation of nonhistone proteins in transcriptional regulation. Mol Endocrinol.2009.23(4):425-33.
[34]Litt M, Qiu Y, Huang S. Histone arginine methylations:their roles in chromatin dynamics and transcriptional regulation. Biosci Rep.2009.29(2):131-41.
[35]Yue WW, Hassler M, Roe SM, Thompson-Vale V, Pearl LH. Insights into histone code syntax from structural and biochemical studies of CARM1 methyltransferase. EMBO J.2007.26(20):4402-12.
[36]Chen D, Ma H, Hong H, et al. Regulation of transcription by a protein methyltransferase. Science.1999. 284(5423):2174-7.
[37]Stallcup MR, Chen D, Koh SS, et al. Co-operation between protein-acetylating and protein-methylating co-activators in transcriptional activation. Biochem Soc Trans.2000.28(4):415-8.
[38]Yadav N, Lee J, Kim J, et al. Specific protein methylation defects and gene expression perturbations in coactivator-associated arginine methyltransferase 1-deficient mice. Proc Natl Acad Sci USA.2003. 100(11):6464-8.
[39]Torres-Padilla ME, Parfitt DE, Kouzarides T, Zernicka-Goetz M. Histone arginine methylation regulates pluripotency in the early mouse embryo. Nature.2007.445(7124):214-8.
[40]Chevillard-Briet M, Trouche D, Vandel L. Control of CBP co-activating activity by arginine methylation. EMBO J.2002.21(20):5457-66.
[41]Lupien M, Eeckhoute J, Meyer CA, et al. Coactivator function defines the active estrogen receptor alpha cistrome. Mol Cell Biol.2009.29(12):3413-23.
[42]Li H, Park S, Kilburn B, et al. Lipopolysaccharide-induced methylation of HuR, an mRNA-stabilizing protein, by CARM1. Coactivator-associated arginine methyltransferase. J Biol Chem.2002.277(47): 44623-30.
[43]Higashimoto K, Kuhn P, Desai D, Cheng X, Xu W. Phosphorylation-mediated inactivation of coactivator-associated arginine methyltransferase 1. Proc Natl Acad Sci U S A.2007.104(30):12318-23.
[44]Hong H, Kao C, Jeng MH, et al. Aberrant expression of CARM1, a transcriptional coactivator of androgen receptor, in the development of prostate carcinoma and androgen-independent status. Cancer.2004.101(1): 83-9.
[45]Majumder S, Liu Y, Ford OH 3rd, Mohler JL, Whang YE. Involvement of arginine methyltransferase CARM1 in androgen receptor function and prostate cancer cell viability. Prostate.2006.66(12):1292-301.
[46]Ou CY, Labonte MJ, Manegold PC, et al. A coactivator role of CARM1 in the dysregulation of {beta}-catenin activity in colorectal cancer cell growth and gene expression. Mol Cancer Res.2011.
[47]Cheng H, Qin Y, Fan H, et al. Overexpression of CARM1 in breast cancer is correlated with poorly characterized clinicopathologic parameters and molecular subtypes. Diagn Pathol.2013.8(1):129.
[1]Kimura Y, Morita SY, Matsuo M, Ueda K. Mechanism of multidrug recognition by MDR1/ABCB1. Cancer Sci.2007.98(9):1303-10.
[2]Chen T. Overcoming drug resistance by regulating nuclear receptors. Adv Drug Deliv Rev.2010.62(13): 1257-64.
[3]Lee CH. Reversing agents for ATP-binding cassette drug transporters. Methods Mol Biol.2010.596: 325-40.
[4]Takeshita A, Inagaki K, Igarashi-Migitaka J, Ozawa Y, Koibuchi N. MDR1-XRE The endocrine disrupting chemical, diethylhexyl phthalate, activates MDR1 gene expression in human colon cancer LS174T cells. J Endocrinol.2006.190(3):897-902.
[5]Geick A, Eichelbaum M, Burk O. Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem.2001.276(18):14581-7.
[6]Geick A, Eichelbaum M, Burk O. MDR1 Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem.2001.276(18):14581-7.
[7]Stallcup MR, Kim JH, Teyssier C, Lee YH, Ma H, Chen D. The roles of protein-protein interactions and protein methylation in transcriptional activation by nuclear receptors and their coactivators. J Steroid Biochem Mol Biol.2003.85(2-5):139-45.
[8]Wysocka J, Allis CD, Coonrod S. Histone arginine methylation and its dynamic regulation. Front Biosci. 2006.11:344-55.
[9]Lee YH, Stallcup MR. Minireview:protein arginine methylation of nonhistone proteins in transcriptional regulation. Mol Endocrinol.2009.23(4):425-33.
[10]Burk O, Arnold KA, Geick A, Tegude H, Eichelbaum M. A role for constitutive androstane receptor in the regulation of human intestinal MDR1 expression. Biol Chem.2005.386(6):503-13.
[11]Mani S, Huang H, Sundarababu S, et al. Activation of the steroid and xenobiotic receptor (human pregnane X receptor) by nontaxane microtubule-stabilizing agents. Clin Cancer Res.2005.11(17):6359-69.
[12]Kleiner HE, Xia X, Sonoda J, et al. Effects of naturally occurring coumarins on hepatic drug-metabolizing enzymes in mice. Toxicol Appl Pharmacol.2008.232(2):337-50.
[13]Chen D, Ma H, Hong H, et al. Regulation of transcription by a protein methyltransferase. Science.1999. 284(5423):2174-7.
[14]Naeem H, Cheng D, Zhao Q, et al. The activity and stability of the transcriptional coactivator p/CIP/SRC-3 are regulated by CARM1-dependent methylation. Mol Cell Biol.2007.27(1):120-34.
[15]Frietze S, Lupien M, Silver PA, Brown M. CARM1 regulates estrogen-stimulated breast cancer growth through up-regulation of E2F1. Cancer Res.2008.68(1):301-6.
[16]El MS, Fabbrizio E, Rodriguez C, et al. Coactivator-associated arginine methyltransferase 1 (CARM1) is a positive regulator of the Cyclin El gene. Proc Natl Acad Sci U S A.2006.103(36):13351-6.
[17]Cheng H, Qin Y, Fan H, et al. Overexpression of CARM1 in breast cancer is correlated with poorly characterized clinicopathologic parameters and molecular subtypes. Diagn Pathol.2013.8(1):129.
[18]Zhang H, Zhang X, Wu X, et al. Interference of Frizzled 1 (CARM1) reverses multidrug resistance in breast cancer cells through the Wnt/beta-catenin pathway. Cancer Lett.2012.323(1):106-13.
[19]Majumder S, Liu Y, Ford OH 3rd, Mohler JL, Whang YE. Involvement of arginine methyltransferase CARM1 in androgen receptor function and prostate cancer cell viability. Prostate.2006.66(12):1292-301.
[20]Barr FD, Krohmer LJ, Hamilton JW, Sheldon LA. Disruption of histone modification and CARM1 recruitment by arsenic represses transcription at glucocorticoid receptor-regulated promoters. PLOS ONE. 2009.4(8):e6766.
[21]Wang H, LeCluyse EL. Role of orphan nuclear receptors in the regulation of drug-metabolising enzymes. Clin Pharmacokinet.2003.42(15):1331-57.
[22]Glass CK, Rosenfeld MG. The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev.2000.14(2):121-41.
[23]Belandia B, Orford RL, Hurst HC, Parker MG. Targeting of SWI/SNF chromatin remodelling complexes to estrogen-responsive genes. EMBO J.2002.21(15):4094-103.
[24]Stallcup MR, Kim JH, Teyssier C, Lee YH, Ma H, Chen D. The roles of protein-protein interactions and protein methylation in transcriptional activation by nuclear receptors and their coactivators. J Steroid Biochem Mol Biol.2003.85(2-5):139-45.
[25]Kawana K, Ikuta T, Kobayashi Y, Gotoh O, Takeda K, Kawajiri K. Molecular mechanism of nuclear translocation of an orphan nuclear receptor, SXR. Mol Pharmacol.2003.63(3):524-31.
[26]Zhou C, Verma S, Blumberg B. The steroid and xenobiotic receptor (SXR), beyond xenobiotic metabolism. Nucl Recept Signal.2009.7:e001.
[27]Synold TW, Dussault I, Forman BM. The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat Med.2001.7(5):584-90.
[28]Basseville A, Preisser L, de Carne Trecesson S, et al.3.778 Irinotecan induces steroid and xenobiotic receptor (SXR) signaling to detoxification pathway in colon cancer cells. Mol Cancer.2011.10:80.
[29]Sonoda J, Pei L, Evans RM. Nuclear receptors:decoding metabolic disease. FEBS Lett.2008.582(1):2-9.
[30]Blumberg B, Sabbagh W Jr, Juguilon H, et al. SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev.1998.12(20):3195-205.
[31]Kimchi-Sarfaty C, Oh JM, Kim IW, et al. A "silent" polymorphism in the MDR1 gene changes substrate specificity. Science.2007.315(5811):525-8.
[32]Kleiner HE, Xia X, Sonoda J, et al. Effects of naturally occurring coumarins on hepatic drug-metabolizing enzymes in mice. Toxicol Appl Pharmacol.2008.232(2):337-50.
[33]Takeshita A, Taguchi M, Koibuchi N, Ozawa Y. Putative role of the orphan nuclear receptor SXR (steroid and xenobiotic receptor) in the mechanism of CYP3A4 inhibition by xenobiotics. J Biol Chem.2002. 277(36):32453-8.
[34]Kim JH, Li H, Stallcup MR. CoCoA, a nuclear receptor coactivator which acts through an N-terminal activation domain of p160 coactivators. Mol Cell.2003.12(6):1537-49.
[35]Chen D, Huang SM, Stallcup MR. Synergistic, p160 coactivator-dependent enhancement of estrogen receptor function by CARM1 and p300. J Biol Chem.2000.275(52):40810-6.
[36]Koh SS, Li H, Lee YH, Widelitz RB, Chuong CM, Stallcup MR. Synergistic coactivator function by coactivator-associated arginine methyltransferase (CARM) 1 and beta-catenin with two different classes of DNA-binding transcriptional activators. J Biol Chem.2002.277(29):26031-5.
[37]Fauquier L, Duboe C, Jore C, Trouche D, Vandel L. Dual role of the arginine methyltransferase CARM 1 in the regulation of c-Fos target genes. FASEB J.2008.22(9):3337-47.
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