title: Lapatinib inhibits CIP2A/PP2A/p-Akt signaling and induces apoptosis in triple negative breast cancer cells.
abstract: We tested the efficacy of lapatinib, a dual tyrosine kinase inhibitor which interrupts the HER2 and epidermal growth factor receptor (EGFR) pathways, in a panel of triple-negative breast cancer (TNBC) cells, and examined the drug mechanism. Lapatinib showed an anti-proliferative effect in HCC 1937, MDA-MB-468, and MDA-MB-231 cell lines. Lapatinib induced significant apoptosis and inhibited CIP2A and p-Akt in a dose and time-dependent manner in the three TNBC cell lines. Overexpression of CIP2A reduced lapatinib-induced apoptosis in MDA-MB-468 cells. In addition, lapatinib increased PP2A activity (in relation to CIP2A inhibition). Moreover, lapatinib-induced apoptosis and p-Akt downregulation was attenuated by PP2A antagonist okadaic acid. Furthermore, lapatinib indirectly decreased CIP2A transcription by disturbing the binding of Elk1 to the CIP2A promoter. Importantly, lapatinib showed anti-tumor activity in mice bearing MDA-MB-468 xenograft tumors, and suppressed CIP2A as well as p-Akt in these xenografted tumors. In summary, inhibition of CIP2A determines the effects of lapatinib-induced apoptosis in TNBC cells. In addition to being a dual tyrosine kinase inhibitor of HER2 and EGFR, lapatinib also inhibits CIP2A/PP2A/p-Akt signaling in TNBC cells.
authors.affiliation: Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.|School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Liu
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Cardinal Tien Hospital, New Taipei City, Taiwan.|School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan.
authors.forename: Ming-Hung
authors.initials: MH
authors.lastname: Hu
authors.affiliation: Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chia-Jung
authors.initials: CJ
authors.lastname: Hsu
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Division of Hematology & Oncology, Department of Medicine, Yang-Ming Branch of Taipei City Hospital, Taipei, Taiwan.
authors.forename: Chun-Teng
authors.initials: CT
authors.lastname: Huang
authors.affiliation: Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Duen-Shian
authors.initials: DS
authors.lastname: Wang
authors.affiliation: Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Wen-Chun
authors.initials: WC
authors.lastname: Tsai
authors.affiliation: Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Chen
authors.affiliation: Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chia-Han
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Department of Pathology, Show Chwan Memorial Hospital, Changhua City, Taiwan.
authors.forename: Pei-Yi
authors.initials: PY
authors.lastname: Chu
authors.affiliation: Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Hsu
authors.affiliation: Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.|School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Ming-Huang
authors.initials: MH
authors.lastname: Chen
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Ling-Ming
authors.initials: LM
authors.lastname: Tseng
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.|National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Kuen-Feng
authors.initials: KF
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001324:Autoantigens; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D000077341:Lapatinib; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008819:Mice, Nude; D011401:Promoter Regions, Genetic / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001324:Autoantigens; D066246:ErbB Receptors; D000077341:Lapatinib; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D054648:Protein Phosphatase 2; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C573112:KIAA1524 protein, mouse; C541485:EGFR protein, mouse; C524056:Erbb2 protein, mouse
keywords: CIP2A; PP2A; apoptosis; lapatinib; triple-negative breast cancer
references.citation: Oncogene. 2009 Oct 29;28(43):3837-46
references.pmid: 19701246
references.citation: PLoS One. 2013 Oct 01;8(10):e75292
references.pmid: 24098375
references.citation: Mol Cancer Ther. 2011 Aug;10(8):1460-9
references.pmid: 21690228
references.citation: Cancer Discov. 2013 Feb;3(2):182-97
references.pmid: 23306062
references.citation: J Natl Cancer Inst. 2009 Jun 3;101(11):793-805
references.pmid: 19470954
references.citation: Int J Cancer. 2016 Feb 1;138(3):525-32
references.pmid: 25628223
references.citation: Med Oncol. 2015 Apr;32(4):87
references.pmid: 25707769
references.citation: Breast Cancer Res. 2013 Nov 12;15(6):R108
references.pmid: 24216290
references.citation: Nat Rev Cancer. 2011 Jun 24;11(7):503-11
references.pmid: 21701512
references.citation: J Cell Biochem. 2013 Aug;114(8):1819-31
references.pmid: 23463670
references.citation: Clin Cancer Res. 2004 Aug 15;10(16):5367-74
references.pmid: 15328174
references.citation: Histol Histopathol. 2012 Jun;27(6):785-92
references.pmid: 22473698
references.citation: Oncogene. 2000 Dec 18;19(55):6503-13
references.pmid: 11175366
references.citation: BMC Res Notes. 2013 Dec 05;6:507
references.pmid: 24304724
references.citation: Biochem Pharmacol. 2013 Feb 1;85(3):356-66
references.pmid: 23178652
references.citation: Haematologica. 2013 May;98(5):729-38
references.pmid: 22983581
references.citation: PLoS One. 2012;7(10 ):e46614
references.pmid: 23071597
references.citation: Oncogene. 2011 May 19;30(20):2367-78
references.pmid: 21258408
references.citation: Breast Cancer Res. 2014 Sep 17;16(5):431
references.pmid: 25228280
references.citation: Cell. 2007 Jul 13;130(1):21-4
references.pmid: 17632053
references.citation: Clin Cancer Res. 2015 Jul 1;21(13):2932-40
references.pmid: 25398453
references.citation: Ann Surg Oncol. 2011 Mar;18(3):857-65
references.pmid: 20842459
references.citation: Mod Pathol. 2014 Sep;27(9):1212-22
references.pmid: 24406864
references.citation: Mol Cancer Ther. 2001 Dec;1(2):85-94
references.pmid: 12467226
references.citation: Biochim Biophys Acta. 2013 Oct;1829(10):1026-33
references.pmid: 23711433
references.citation: J Gastrointest Surg. 2012 May;16(5):1037-47
references.pmid: 22328001
references.citation: J Exp Clin Cancer Res. 2010 Oct 21;29:136
references.pmid: 20964854
references.citation: PLoS One. 2011;6(5):e20159
references.pmid: 21655278
references.citation: Oral Oncol. 2012 Jul;48(7):585-93
references.pmid: 22342571
references.citation: Tumour Biol. 2012 Dec;33(6):2299-306
references.pmid: 22923389
references.citation: Med Oncol. 2012 Sep;29(3):1643-7
references.pmid: 21874565
references.citation: Breast Cancer. 2014 Jan;21(1):66-74
references.pmid: 22481575
references.citation: Clin Ther. 2009;31 Pt 2:2332-48
references.pmid: 20110044
references.citation: FEBS Lett. 2011 Mar 9;585(5):755-60
references.pmid: 21241697
references.citation: Mol Cell Proteomics. 2012 Dec;11(12):1741-57
references.pmid: 22964224
references.citation: Oncotarget. 2015 Aug 14;6(23):19661-70
references.pmid: 25965834
references.citation: Cancer Res. 2006 Feb 1;66(3):1630-9
references.pmid: 16452222
references.citation: Cell. 2007 Jul 13;130(1):51-62
references.pmid: 17632056
references.citation: Cancer Res. 2013 Jan 1;73(1):450-8
references.pmid: 23288917
references.citation: Mol Pharmacol. 2013 Apr;83(4):857-69
references.pmid: 23355539
references.citation: Clin Ther. 2008 Aug;30(8):1426-47
references.pmid: 18803986
references.citation: Expert Opin Investig Drugs. 2009 Nov;18(11):1735-51
references.pmid: 19780706
references.citation: J Clin Oncol. 2005 Apr 10;23(11):2502-12
references.pmid: 15684311
references.citation: PLoS One. 2011 Mar 22;6(3):e17979
references.pmid: 21445343
references.citation: Oncotarget. 2014 Jul 15;5(13):4581-602
references.pmid: 25015035
references.citation: Breast Cancer Res. 2012 Apr 26;14(2):R68
references.pmid: 22537901
references.citation: Clin Cancer Res. 2009 Aug 15;15(16):5092-100
references.pmid: 19671842
references.citation: J Clin Oncol. 2012 Jun 1;30(16):1989-95
references.pmid: 22493419
references.citation: J Biol Chem. 2013 Jul 12;288(28):20488-98
references.pmid: 23720781
references.citation: N Engl J Med. 2006 Dec 28;355(26):2733-43
references.pmid: 17192538
references.citation: Med Oncol. 2013 Mar;30(1):406
references.pmid: 23275123
references.citation: Breast Cancer Res Treat. 2011 Jan;125(1):107-14
references.pmid: 20936340
references.citation: Mol Cancer. 2014 Oct 19;13:236
references.pmid: 25326651
references.citation: Genes Cells. 2013 Feb;18(2):110-22
references.pmid: 23279183
references.citation: Cancer Res. 2013 Nov 15;73(22):6548-53
references.pmid: 24204027
references.citation: Transcription. 2012 Nov-Dec;3(6):323-35
references.pmid: 23117818
references.citation: Lancet Oncol. 2014 Sep;15(10):1137-46
references.pmid: 25130998
references.citation: Lancet Oncol. 2013 Nov;14(12):1183-92
references.pmid: 24095300
references.citation: J Cell Biochem. 2004 Apr 1;91(5):896-903
references.pmid: 15034925
references.citation: Cancer Med. 2015 Jun;4(6):914-24
references.pmid: 25693514
references.citation: Clin Cancer Res. 2008 Jun 15;14(12):3722-8
references.pmid: 18559589