title: Mechanisms of Gefitinib-mediated reversal of tamoxifen resistance in MCF-7 breast cancer cells by inducing ERα re-expression.
abstract: Estrogen receptor (ER)-positive breast cancer patients may turn ER-negative and develop acquired drug resistance, which compromises the efficacy of endocrine therapy. By investigating the phenomenon that gefitinib can re-sensitise tamoxifen (TAM)-resistant MCF-7 breast cancer cells (MCF-7/TAM) to TAM, the present study verified that gefitinib could reverse the acquired drug resistance in endocrine therapy and further explored the underlying mechanism.ERα-negative MCF-7/TAM cells were established. Upon treating the cells with gefitinib, the mRNA and protein levels of ERα and ERβ, as well as the expression of molecules involved in the MAPK pathway, were examined using the RT-PCR and immunocytochemistry. The RT-PCR results showed that the mRNA levels of ERα and ERβ in MCF-7/TAM cells were up-regulated following gefitinib treatment; specifically, ERα was re-expressed, and ERβ expression was up-regulated. The expression of molecules involved in the MAPK pathway, including RAS, MEK1/2, and p-ERK1/2, in MCF-7/TAM cells was significantly up-regulated, compared with MCF-7 cells. After the gefitinib treatment, the expression levels of MEK1/2 and p-ERK1/2 were significantly down-regulated. ERα loss is the primary cause for TAM resistance. Gefitinib reverses TAM resistance primarily by up-regulating the ERα mRNA level and inducing the re-expression of ERα. The MAPK pathway plays a key role in ERα re-expression.
authors: Department of Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong 250117, P. R. China.
authors: Xia
authors: X
authors: Zhang
authors: Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P. R. China.
authors: Bin
authors: B
authors: Zhang
authors: Department of Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong 250117, P. R. China.
authors: Jie
authors: J
authors: Liu
authors: Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P. R. China.
authors: Jiwei
authors: J
authors: Liu
authors: Department of Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong 250117, P. R. China.
authors: Changzheng
authors: C
authors: Li
authors: Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong 250117, P. R. China.
authors: Wei
authors: W
authors: Dong
authors: Department of Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong 250117, P. R. China.
authors: Shu
authors: S
authors: Fang
authors: Department of Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong 250117, P. R. China.
authors: Minmin
authors: M
authors: Li
authors: Department of Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong 250117, P. R. China.
authors: Bao
authors: B
authors: Song
authors: Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi 541001, P. R. China.
authors: Bo
authors: B
authors: Tang
authors: Department of Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong 250117, P. R. China.
authors: Zhehai
authors: Z
authors: Wang
authors: Department of Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, P. R. China.
authors: Yang
authors: Y
authors: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D061986:MCF-7 Cells; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D011799:Quinazolines; D012333:RNA, Messenger; D013629:Tamoxifen; C482128:MAP2K2 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D000077156:Gefitinib
references: Clin Cancer Res. 2007 Dec 1;13(23):7029-36
references: 18056179
references: Clin Cancer Res. 2007 Apr 1;13(7):1987-94
references: 17404078
references: J Cancer Res Clin Oncol. 2008 Aug;134(8):883-90
references: 18264725
references: Cancer Res. 2008 Sep 15;68(18):7493-501
references: 18794137
references: World J Gastroenterol. 2009 Jan 28;15(4):431-40
references: 19152447
references: Breast Cancer Res Treat. 2009 Sep;117(2):253-9
references: 18814026
references: Clin Biochem. 2010 Mar;43(4-5):380-6
references: 19961842
references: CA Cancer J Clin. 2011 Jan-Feb;61(1):8-30
references: 21205832
references: Clin Cancer Res. 2011 Mar 1;17(5):1147-59
references: 21220480
references: Chin Med J (Engl). 2011 Nov;124(22):3834-7
references: 22340252
references: Breast Cancer Res Treat. 2012 Nov;136(2):399-406
references: 23053650
references: Cancer. 2000 Oct 15;89(8):1732-8
references: 11042568
references: Endocr Relat Cancer. 2001 Mar;8(1):47-61
references: 11350726
references: Mol Endocrinol. 2001 Aug;15(8):1344-59
references: 11463858
references: Oncogene. 2001 Jul 12;20(31):4209-18
references: 11464287
references: Mol Cancer Ther. 2002 Jul;1(9):707-17
references: 12479367
references: Mol Cancer Res. 2003 Feb;1(4):300-11
references: 12612058
references: Int J Cancer. 2003 Nov 10;107(3):353-8
references: 14506733
references: Clin Cancer Res. 2004 Jan 1;10(1 Pt 2):337S-45S
references: 14734489
references: Proc Natl Acad Sci U S A. 2004 Feb 10;101(6):1566-71
references: 14745018
references: J Natl Cancer Inst. 2004 Jun 16;96(12):926-35
references: 15199112
references: J Clin Oncol. 2004 Aug 1;22(15):3199-200; author reply 3200-1
references: 15284276
references: Cancer Res. 1994 May 15;54(10):2552-5
references: 8168078
references: EMBO J. 1996 Mar 15;15(6):1292-300
references: 8635462
references: Science. 1997 Sep 5;277(5331):1508-10
references: 9278514
references: Anticancer Drugs. 1997 Nov;8(10):911-30
references: 9436634
references: Lancet. 1998 May 16;351(9114):1451-67
references: 9605801
references: Cancer Res. 1998 Jun 15;58(12):2515-9
references: 9635570
references: J Clin Oncol. 1999 May;17(5):1474-81
references: 10334533
references: Clin Cancer Res. 2004 Nov 15;10(22):7490-9
references: 15569979
references: Cancer Res. 2005 Jun 15;65(12):5380-9
references: 15958587
references: Endocr Relat Cancer. 2005 Jul;12 Suppl 1:S75-84
references: 16113101
references: Int J Cancer. 2006 Jan 1;118(1):209-14
references: 16003751
references: Cancer Sci. 2006 Feb;97(2):155-62
references: 16441427
references: J Cell Physiol. 2006 May;207(2):420-7
references: 16419029
references: Cancer Res. 2006 Apr 1;66(7):3903-11
references: 16585219
references: Taiwan J Obstet Gynecol. 2006 Dec;45(4):307-12
references: 17175487
references: Clin Imaging. 2007 Sep-Oct;31(5):306-12
references: 17825737
references: Chin Med J (Engl). 2007 Oct 5;120(19):1710-5
references: 17935676
references: Target Oncol. 2013 Jun;8(2):137-43
references: 23609057
references: Tumour Biol. 2014 Feb;35(2):1275-86
references: 24014089
references: J Clin Pathol. 2008 Feb;61(2):197-203
references: 18223096