Ad-p53逆转乳腺癌耐药性及其对P-gp、TOPOⅡ和GST-π表达的影响
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摘要
目的探讨腺病毒介导的p53基因(Ad-p53)对人乳腺癌阿霉素耐药细胞株MCF-7/Adr多药耐药的逆转作用及其对耐药相关蛋白P-gp、TOPOⅡ和GST-π表达的影响。
方法以人乳腺癌MCF-7细胞及其阿霉素耐药株MCF-7/Adr为实验对象,通过腺病毒介导的野生型p53基因转染乳腺癌耐药细胞株MCF-7/Adr,cck-8法检测MCF-7/Adr细胞对阿霉素的耐药倍数及基因转染后的耐药逆转倍数;采用免疫荧光组织化学法及western blot检测Ad-p53作用前后MCF-7/Adr细胞内P-gp、TOPOⅡ和GST-π蛋白表达的变化。
结果50 MOI Ad-p53能使阿霉素对MCF-7/Adr细胞IC_(50)由(4.54±0.91)μg/ml降到(0.26±0.11)μg/ml,逆转耐药倍数为18.1倍(P<0.01);免疫荧光组织化学及western blot显示P-gp、GST-π蛋白表达量下降,TOPOⅡ未见明显变化。
结论Ad-p53对乳腺癌耐药细胞株MCF-7/Adr的耐药性有明显的逆转作用,其机制与下调P-gp和GST-π表达有关。
Objective
To explore whether adenovirus mediated p53 gene (Ad-p53) could reverse multidrug resistance(MDR) of human breast cancer and its impacts on the expressions of P-gp、TOPOⅡand GST-π.
Methods
In this study, adriamycin-resistant human breast carcinoma cells (MCF-7/Adr) and its parental cells (MCF-7) were used to determine the effect of Ad-p53. Wt-p53 gene was transfected into MCF-7/Adr cell line through adenovirus-mediated. Cck-8 assay was adopted to evaluate the cytotoxicity of adriamycin. Immunofluorescence histochemical and western blot were performed to observe the expression of P-glycoprotein(P-gp)、TopoismeraseⅡ(TOPOⅡ) and GST-π.
Results
After transfection with 50 MOI Ad-p53, the 50% inhibitory concentration (IC_(50)) of adriamycin to MCF-7/Adr cells was decreased from (4.54±0.91)μg/ml to (0.26±0.11)μg/ml, and the chemosensitivity increased 18.1 times (P<0.01). Immunofluorescence histochemical and western blot analysis showed that the expressions of P-gp and GST-πwere down-regulated, and there is no significant change of TOPOⅡexpression.
Conclusions
Ad-p53 could reverse multidrug resistance of MCF-7/Adr cells through the down-regulation of P-gp and GST-πexpressions.
方法以人乳腺癌MCF-7细胞及其阿霉素耐药株MCF-7/Adr为实验对象,通过腺病毒介导的野生型p53基因转染乳腺癌耐药细胞株MCF-7/Adr,cck-8法检测MCF-7/Adr细胞对阿霉素的耐药倍数及基因转染后的耐药逆转倍数;采用免疫荧光组织化学法及western blot检测Ad-p53作用前后MCF-7/Adr细胞内P-gp、TOPOⅡ和GST-π蛋白表达的变化。
结果50 MOI Ad-p53能使阿霉素对MCF-7/Adr细胞IC_(50)由(4.54±0.91)μg/ml降到(0.26±0.11)μg/ml,逆转耐药倍数为18.1倍(P<0.01);免疫荧光组织化学及western blot显示P-gp、GST-π蛋白表达量下降,TOPOⅡ未见明显变化。
结论Ad-p53对乳腺癌耐药细胞株MCF-7/Adr的耐药性有明显的逆转作用,其机制与下调P-gp和GST-π表达有关。
Objective
To explore whether adenovirus mediated p53 gene (Ad-p53) could reverse multidrug resistance(MDR) of human breast cancer and its impacts on the expressions of P-gp、TOPOⅡand GST-π.
Methods
In this study, adriamycin-resistant human breast carcinoma cells (MCF-7/Adr) and its parental cells (MCF-7) were used to determine the effect of Ad-p53. Wt-p53 gene was transfected into MCF-7/Adr cell line through adenovirus-mediated. Cck-8 assay was adopted to evaluate the cytotoxicity of adriamycin. Immunofluorescence histochemical and western blot were performed to observe the expression of P-glycoprotein(P-gp)、TopoismeraseⅡ(TOPOⅡ) and GST-π.
Results
After transfection with 50 MOI Ad-p53, the 50% inhibitory concentration (IC_(50)) of adriamycin to MCF-7/Adr cells was decreased from (4.54±0.91)μg/ml to (0.26±0.11)μg/ml, and the chemosensitivity increased 18.1 times (P<0.01). Immunofluorescence histochemical and western blot analysis showed that the expressions of P-gp and GST-πwere down-regulated, and there is no significant change of TOPOⅡexpression.
Conclusions
Ad-p53 could reverse multidrug resistance of MCF-7/Adr cells through the down-regulation of P-gp and GST-πexpressions.
引文
[1]沈镇宙主编.乳腺肿瘤学[M].上海科技出版社. 2005; 4:228-234.
[2] Wang L, Yang CP, Horwitz SB, et al. Reversal of the human murine multidrug- resistance phenotype with megestrol acetate[J]. Cancer Chemother Pharmcol, 1994; 34(2):96-102.
[3] Kartner N, Riordan JR, Ling V. Cell surface P-glycoprotein associated with multidrug resistance in mammalian cell lines[J]. Science,1983;221(4617):1285-1288.
[4] Trock BJ, Leonessa F, Clarke R, et al. Multidrug resistance in breast cancer:a meta-analysis of MDR1/P-gp expression and its possible functional significance[J].J Natl Cancer Inst,1997;89(13):917-931.
[5] Linn SC, Honkoop AH, Hoekman K,et al.p53 and P-glycoprotein are often co-expressed and are associated with poor prognosis in breast cancer[J]. Br J Cancer, 1996;74(1):63-68.
[6] Thomas H, Coley HM. Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting P-glycoprotein[J].Cancer Control. 2003;10(2): 159-165.
[7] Sotiriou C , Powles TJ , Dowsett M, et al .Gene expression profiles derived from fine needle aspiration correlate with response to systemic chernotherapy in breast cancer [J]. Breast Cancer Res.2002;4(3):R3.
[8] Silva JM, Gonzalez R, Dominguez G, et al. Tp53 gene mutations in plasma DNA of cancer patients [J]. Genes Chromosomes Cancer,1999;24 (2):160-161.
[9] Bharti AC, Aggarwal BB. Nuclear factor kappa B and cancer: Its role in prevention and therapy[J].Biochem Pharmacol,2002;64(526):883-888.
[10] Chin KV, Ueda K,Pastan I,et al. Modulation of activity of the promoter of the human mdr1 gene by Ras and p53[J].Science. 1992; 255(5043): 459-462.
[11] Yoo GH, Piechocki MP, Oliver J, et al. Enhancement of Ad-p53 therapy with docetaxel in head and neck cancer[J].Laryngoscopy. 2004;114(11):1871-1879.
[12] Liu B, Zhang H, Zhou G, et al. Adenovirus-mediated p53 gene transfer sensitizes hepatocellular carcinoma cells to heavy-ion radiation[J].J Gastroenterol. 2007;42(2): 140-145.
[13]戚晓东,杨之斌,韩德民等.“今又生”治疗晚期恶性肿瘤的疗效观察(附23例) [J].现代肿瘤医学.2006;14(10):1295-1297.
[14] Ogretmen B, Safa AR. Expression of the mutated p53 tumor suppressor protein and its molecular and biochemical characterization in multi-drug resistant MCF-7/Adr human breast cancer cells[J]. Oncogene.1997;14(4):499-506.
[15] Ranganathan S, Tew KD. Immunohistochemical localization of glutathione S-transferases alpha, mu, and pi in normal tissue and carcinomas from human colon[J]. Carcinogenesis. 1991;12(12): 2383-2387.
[16] Tew KD. Glutathione-associated enzyme in anticancer drug resistance[J]. Cancer Res. 1994;54(16):4313-4320.
[17]李杰,许良中,吴炅.三种耐药基因蛋白表达在乳腺癌中的临床意义[J].癌症. 2001;20 (8) :866-868.
[18] Beck J, Bohnet B, Brger D, et al. Multiple gene expression analysis reveals distinct differences between G2 and G3 stage breast cancers, and correlation of PKC eta with MDR1,MRP and LRP gene expression[J].Br J Cancer. 1998;77(1):87-91.
[19] Coon JS, Marcus E, Gupta-Burt S, et al. Amplification and overexpression of topoisomeraseⅡalpha predict response to anthracycline-based therapy in locally advanced breast cancer[J]. Clin Cancer Res. 2002; 8 (4):1061-1067.
[20] Horio Y, Hasegawa Y, Sekido Y, et al. Synergistic effects of adenovirus expressing wild type p53 on chemosensitivity of non-small cell lung cancer cells. Cancer Gene Ther. 2000;7(4):537-544.
[21] Baek JH, Agarwalm L, Tubbs RR, et al. In vivo recombinant Adenovirus mediated p53 gene therapy in a syngeneic rat model for colorectal cancer[J].J Korean Med Sci. 2004;19(6):834-841.
[22] Zhan MC, Yu DH, Lang AQ, et al. Wild type p53 sensitizes soft tissue sarcoma cells to doxorubicin by down-regulating multidrug resistance-1 expression[J].Cancer. 2001;92(6):1556-1566.
[23]何时知,戚晓东,张晓明等.腺病毒介导p53基因逆转乳腺癌耐药的实验研究[J].中华医学杂志.2007;87(41): 2935-2937.
[1] Gottesmana M, Ling V. The molecular basis of multidrug sesistance in cancer:The early years of P-glycoprotein research[J].FEBS Letters,2006; 580 (4):998-1009.
[2] Cole SP, Bhardwaj G, Gerlach JH, et al. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line[J].Science,1992;258(5088): 1650-1654.
[3] Hennessy M, Spiers JP.A primer on the mechanics of P-glycoprotein the multidrug transporter [J].Pharmacological Research, 2007; 55 (1):1-15.
[4] Stein WD. Kinetics of the multidrug transporter (P-glycoprotein) and its reversal [J]. Physiol Rev,1997;77(2):545-590.
[5] Ghauharali RI, Westerhoff HV, Dekker H, et al. Saturable P-glycoprotein kinetics assayed by fluorescence studies of drug efflux from suspended human KB8-5 cells[J]. Biochim Biophys Acta, 1996;1278:213-222.
[6] Trock BJ, Leonessa F, Clarke R. Multidrug resistance in breast cancer: a meta-analysis of MDR1/gp170 expression and its possible functional significance[J]. J Natl Cancer Inst, 1997; 89 (13):917-931.
[7]李恩孝,李毅,李蓉等.转移性乳腺癌P糖蛋白表达与化疗疗效的关系[J].癌症,2002;21 (4):430-432.
[8] Lacave R, Coulet F, Ricci S, et al. Comparative evaluation by semi quantitative reverse transcriptase polymerase chain reaction of MDR1, MRP and GSTp gene expression in breast carcinomas[J].Br J Cancer,1998;77 (5):694-702.
[9] Kanzaki A, Toi M, Nakayama K, et al. Expression of multidrug resistance-related transporters in human breast carcinoma[J]. Jpn J Cancer Res, 2001; 92(4):452-458.
[10] Scheper RJ, Broxterman HJ, Scheffer GL, et al. Over-expression of a M(r) 110000 vesicular protein in non p-glycoprotein mediated multidrug resistance[J].Cancer Res, 1993;53 (7):1475-1479.
[11] Pohl G, Filipits M, Suchomel RW, et al. Expression of the lung resistance protein (LRP) in primary breast cancer [J]. Anticancer Res, 1999; 19(6B):5051-5055.
[12] Cooray HC, Blackmore CG, Maskell L, et al. Localisation of breast cancer resistance protein in microvessel endothelium of human brain [J]. Neuroreport, 2002; 13(16):2059-2063.
[13] Ejendal KF, Hrycyna CA. Multidrug resistance and cancer: the role of the human ABC transporter ABCG2 [J]. Curr Protein Pept Sci, 2002; 3(5):503-511.
[14]李杰,许良中,吴炅.三种耐药基因蛋白表达在乳腺癌中的临床意义[J].癌症,2001;20(8):866-868.
[15] Beck J, Bohnet B, Brger D, et al. Multiple gene expression analysis reveals distinct differences between G2 and G3
[20] Yu D, Hung MC. Role of erbB2 in breast cancer chemosensitivity [J]. Bioessays, stage breast cancers, and correlation of PKC eta with MDR1, MRP and LRP gene expression[J].Br J Cancer,1998;77(1):87-91.
[16] Linn SC, Honkoop AH, Hoekman K, et al. p53 and P-glycoprotein are often co-expressed and are associated with poor prognosis in breast cancer[J].Br J Cancer, 1996;74(1):63-68.
[17] Osmak M, Brozovic A, Ambriovic-Ristov A, et al. Inhibition of apoptosis is the cause of resistance to doxorubicin in human breast adenocarcinoma cells [J]. Neoplasma, 1998; 45(4):223-230.
[18] Friedrich K, Wieder T, Von Haefen C, et al. Over-expression of caspase-3 restores sensitivity for drug-induced apoptosis in breast cancer cell lines with acquired drug resistance[J].Oncogene, 2001;20(22):2749-2760.
[19] Seth P, Katayose D, Li Z, et al. A recombinant adenovirus expressing wild type p53 induces apoptosis in drug-resistant cancers [J].Cancer Gene Ther, 1997; 4(6):383 -390.2000; 22(7):673-680.
[21] Witters LM, Santala SM, Engle L, et al. Decreased response to paclitaxel versus docetaxel in HER-2/neu transfected human breast cancer cells[J]. Am J Clin Oncol, 2003;26(1):50-54.
[22] Tari AM, Lim SJ, Hung MC, et al. Her2/neu induces all-trans retinoic acid (ATRA) resistance in breast cancer cells [J]. Oncogene, 2002;21(34):5224-5232.
[23] Knowlden JM, Hutcheson IR, Jones HE, et al. Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells[J].Endocrinology,2003;144(3):1032- 1044.
[24] Konecny G, Fritz M ,Untch M ,et al. HER-2/neu over-expression and in vitro chemosensitivity to CMF and FEC in primary breast cancer[J].Breast Cancer Res Treat,2001;69(1):53-63.
[25] Kim R, Tanabe K, Uchida Y, et al. The role of HER-2 oncoprotein in drug- sensitivity in breast cancer[J]. Oncol Rep, 2002; 9(1):3-9.
[26] Yu D, Liu B, Jing T, et al. Over-expression of both p185 c-erbB2 and p170 mdr-1 renders breast cancer cells highly resistant to taxol [J].Oncogene,1998; 16(16):2087-2094.
[27] Yu D, Liu B, Tan M, et al. Overexpression of c-erbB-2/neu in breast cells increased resistance to Taxol via mdr-1-independent mechanisms [J]. Oncogene,1996; 13(6):1359-1365.
[28] Tanabe K, Kim R, Inoue H, et al. Antisense Bcl-2 and HER-2 oligonucleotide treatment of breast cancer cells enhances their sensitivity to anticancer drugs[J]. Int J Oncol, 2003;22 (4):875-881.
[29] Yu D. Mechanisms of ErbB-2mediated paclitaxel resistance and trastuzumab- mediated paclitaxel sensitization in ErBb-2 over-expressing breast cancers[J].SeminOncol,2001;28 (5 Suppl 16):12-17.
[2] Wang L, Yang CP, Horwitz SB, et al. Reversal of the human murine multidrug- resistance phenotype with megestrol acetate[J]. Cancer Chemother Pharmcol, 1994; 34(2):96-102.
[3] Kartner N, Riordan JR, Ling V. Cell surface P-glycoprotein associated with multidrug resistance in mammalian cell lines[J]. Science,1983;221(4617):1285-1288.
[4] Trock BJ, Leonessa F, Clarke R, et al. Multidrug resistance in breast cancer:a meta-analysis of MDR1/P-gp expression and its possible functional significance[J].J Natl Cancer Inst,1997;89(13):917-931.
[5] Linn SC, Honkoop AH, Hoekman K,et al.p53 and P-glycoprotein are often co-expressed and are associated with poor prognosis in breast cancer[J]. Br J Cancer, 1996;74(1):63-68.
[6] Thomas H, Coley HM. Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting P-glycoprotein[J].Cancer Control. 2003;10(2): 159-165.
[7] Sotiriou C , Powles TJ , Dowsett M, et al .Gene expression profiles derived from fine needle aspiration correlate with response to systemic chernotherapy in breast cancer [J]. Breast Cancer Res.2002;4(3):R3.
[8] Silva JM, Gonzalez R, Dominguez G, et al. Tp53 gene mutations in plasma DNA of cancer patients [J]. Genes Chromosomes Cancer,1999;24 (2):160-161.
[9] Bharti AC, Aggarwal BB. Nuclear factor kappa B and cancer: Its role in prevention and therapy[J].Biochem Pharmacol,2002;64(526):883-888.
[10] Chin KV, Ueda K,Pastan I,et al. Modulation of activity of the promoter of the human mdr1 gene by Ras and p53[J].Science. 1992; 255(5043): 459-462.
[11] Yoo GH, Piechocki MP, Oliver J, et al. Enhancement of Ad-p53 therapy with docetaxel in head and neck cancer[J].Laryngoscopy. 2004;114(11):1871-1879.
[12] Liu B, Zhang H, Zhou G, et al. Adenovirus-mediated p53 gene transfer sensitizes hepatocellular carcinoma cells to heavy-ion radiation[J].J Gastroenterol. 2007;42(2): 140-145.
[13]戚晓东,杨之斌,韩德民等.“今又生”治疗晚期恶性肿瘤的疗效观察(附23例) [J].现代肿瘤医学.2006;14(10):1295-1297.
[14] Ogretmen B, Safa AR. Expression of the mutated p53 tumor suppressor protein and its molecular and biochemical characterization in multi-drug resistant MCF-7/Adr human breast cancer cells[J]. Oncogene.1997;14(4):499-506.
[15] Ranganathan S, Tew KD. Immunohistochemical localization of glutathione S-transferases alpha, mu, and pi in normal tissue and carcinomas from human colon[J]. Carcinogenesis. 1991;12(12): 2383-2387.
[16] Tew KD. Glutathione-associated enzyme in anticancer drug resistance[J]. Cancer Res. 1994;54(16):4313-4320.
[17]李杰,许良中,吴炅.三种耐药基因蛋白表达在乳腺癌中的临床意义[J].癌症. 2001;20 (8) :866-868.
[18] Beck J, Bohnet B, Brger D, et al. Multiple gene expression analysis reveals distinct differences between G2 and G3 stage breast cancers, and correlation of PKC eta with MDR1,MRP and LRP gene expression[J].Br J Cancer. 1998;77(1):87-91.
[19] Coon JS, Marcus E, Gupta-Burt S, et al. Amplification and overexpression of topoisomeraseⅡalpha predict response to anthracycline-based therapy in locally advanced breast cancer[J]. Clin Cancer Res. 2002; 8 (4):1061-1067.
[20] Horio Y, Hasegawa Y, Sekido Y, et al. Synergistic effects of adenovirus expressing wild type p53 on chemosensitivity of non-small cell lung cancer cells. Cancer Gene Ther. 2000;7(4):537-544.
[21] Baek JH, Agarwalm L, Tubbs RR, et al. In vivo recombinant Adenovirus mediated p53 gene therapy in a syngeneic rat model for colorectal cancer[J].J Korean Med Sci. 2004;19(6):834-841.
[22] Zhan MC, Yu DH, Lang AQ, et al. Wild type p53 sensitizes soft tissue sarcoma cells to doxorubicin by down-regulating multidrug resistance-1 expression[J].Cancer. 2001;92(6):1556-1566.
[23]何时知,戚晓东,张晓明等.腺病毒介导p53基因逆转乳腺癌耐药的实验研究[J].中华医学杂志.2007;87(41): 2935-2937.
[1] Gottesmana M, Ling V. The molecular basis of multidrug sesistance in cancer:The early years of P-glycoprotein research[J].FEBS Letters,2006; 580 (4):998-1009.
[2] Cole SP, Bhardwaj G, Gerlach JH, et al. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line[J].Science,1992;258(5088): 1650-1654.
[3] Hennessy M, Spiers JP.A primer on the mechanics of P-glycoprotein the multidrug transporter [J].Pharmacological Research, 2007; 55 (1):1-15.
[4] Stein WD. Kinetics of the multidrug transporter (P-glycoprotein) and its reversal [J]. Physiol Rev,1997;77(2):545-590.
[5] Ghauharali RI, Westerhoff HV, Dekker H, et al. Saturable P-glycoprotein kinetics assayed by fluorescence studies of drug efflux from suspended human KB8-5 cells[J]. Biochim Biophys Acta, 1996;1278:213-222.
[6] Trock BJ, Leonessa F, Clarke R. Multidrug resistance in breast cancer: a meta-analysis of MDR1/gp170 expression and its possible functional significance[J]. J Natl Cancer Inst, 1997; 89 (13):917-931.
[7]李恩孝,李毅,李蓉等.转移性乳腺癌P糖蛋白表达与化疗疗效的关系[J].癌症,2002;21 (4):430-432.
[8] Lacave R, Coulet F, Ricci S, et al. Comparative evaluation by semi quantitative reverse transcriptase polymerase chain reaction of MDR1, MRP and GSTp gene expression in breast carcinomas[J].Br J Cancer,1998;77 (5):694-702.
[9] Kanzaki A, Toi M, Nakayama K, et al. Expression of multidrug resistance-related transporters in human breast carcinoma[J]. Jpn J Cancer Res, 2001; 92(4):452-458.
[10] Scheper RJ, Broxterman HJ, Scheffer GL, et al. Over-expression of a M(r) 110000 vesicular protein in non p-glycoprotein mediated multidrug resistance[J].Cancer Res, 1993;53 (7):1475-1479.
[11] Pohl G, Filipits M, Suchomel RW, et al. Expression of the lung resistance protein (LRP) in primary breast cancer [J]. Anticancer Res, 1999; 19(6B):5051-5055.
[12] Cooray HC, Blackmore CG, Maskell L, et al. Localisation of breast cancer resistance protein in microvessel endothelium of human brain [J]. Neuroreport, 2002; 13(16):2059-2063.
[13] Ejendal KF, Hrycyna CA. Multidrug resistance and cancer: the role of the human ABC transporter ABCG2 [J]. Curr Protein Pept Sci, 2002; 3(5):503-511.
[14]李杰,许良中,吴炅.三种耐药基因蛋白表达在乳腺癌中的临床意义[J].癌症,2001;20(8):866-868.
[15] Beck J, Bohnet B, Brger D, et al. Multiple gene expression analysis reveals distinct differences between G2 and G3
[20] Yu D, Hung MC. Role of erbB2 in breast cancer chemosensitivity [J]. Bioessays, stage breast cancers, and correlation of PKC eta with MDR1, MRP and LRP gene expression[J].Br J Cancer,1998;77(1):87-91.
[16] Linn SC, Honkoop AH, Hoekman K, et al. p53 and P-glycoprotein are often co-expressed and are associated with poor prognosis in breast cancer[J].Br J Cancer, 1996;74(1):63-68.
[17] Osmak M, Brozovic A, Ambriovic-Ristov A, et al. Inhibition of apoptosis is the cause of resistance to doxorubicin in human breast adenocarcinoma cells [J]. Neoplasma, 1998; 45(4):223-230.
[18] Friedrich K, Wieder T, Von Haefen C, et al. Over-expression of caspase-3 restores sensitivity for drug-induced apoptosis in breast cancer cell lines with acquired drug resistance[J].Oncogene, 2001;20(22):2749-2760.
[19] Seth P, Katayose D, Li Z, et al. A recombinant adenovirus expressing wild type p53 induces apoptosis in drug-resistant cancers [J].Cancer Gene Ther, 1997; 4(6):383 -390.2000; 22(7):673-680.
[21] Witters LM, Santala SM, Engle L, et al. Decreased response to paclitaxel versus docetaxel in HER-2/neu transfected human breast cancer cells[J]. Am J Clin Oncol, 2003;26(1):50-54.
[22] Tari AM, Lim SJ, Hung MC, et al. Her2/neu induces all-trans retinoic acid (ATRA) resistance in breast cancer cells [J]. Oncogene, 2002;21(34):5224-5232.
[23] Knowlden JM, Hutcheson IR, Jones HE, et al. Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells[J].Endocrinology,2003;144(3):1032- 1044.
[24] Konecny G, Fritz M ,Untch M ,et al. HER-2/neu over-expression and in vitro chemosensitivity to CMF and FEC in primary breast cancer[J].Breast Cancer Res Treat,2001;69(1):53-63.
[25] Kim R, Tanabe K, Uchida Y, et al. The role of HER-2 oncoprotein in drug- sensitivity in breast cancer[J]. Oncol Rep, 2002; 9(1):3-9.
[26] Yu D, Liu B, Jing T, et al. Over-expression of both p185 c-erbB2 and p170 mdr-1 renders breast cancer cells highly resistant to taxol [J].Oncogene,1998; 16(16):2087-2094.
[27] Yu D, Liu B, Tan M, et al. Overexpression of c-erbB-2/neu in breast cells increased resistance to Taxol via mdr-1-independent mechanisms [J]. Oncogene,1996; 13(6):1359-1365.
[28] Tanabe K, Kim R, Inoue H, et al. Antisense Bcl-2 and HER-2 oligonucleotide treatment of breast cancer cells enhances their sensitivity to anticancer drugs[J]. Int J Oncol, 2003;22 (4):875-881.
[29] Yu D. Mechanisms of ErbB-2mediated paclitaxel resistance and trastuzumab- mediated paclitaxel sensitization in ErBb-2 over-expressing breast cancers[J].SeminOncol,2001;28 (5 Suppl 16):12-17.