title: The role of HER2 in cancer therapy and targeted drug delivery.
abstract: HER2 is highly expressed in a significant proportion of breast cancer, ovarian cancer, and gastric cancer. Since the discovery of its role in tumorigenesis, HER2 has received great attention in cancer research during the past two decades. Successful development of the humanized monoclonal anti-HER2 antibody (Trastuzumab) for the treatment of breast cancer further spurred scientists to develop various HER2 specific antibodies, dimerization inhibitors and kinase inhibitors for cancer therapy. On the other hand, the high expression of HER2 and the accessibility of its extracellular domain make HER2 an ideal target for the targeted delivery of anti-tumor drugs as well as imaging agents. Although there is no natural ligand for HER2, artificial ligands targeting HER2 have been developed and applied in various targeted drug delivery systems. The emphasis of this review is to elucidate the roles of HER2 in cancer therapy and targeted drug delivery. The structure and signal pathway of HER2 will be briefly described. The role of HER2 in tumorigenesis and its relationship with other tumor markers will be discussed. For the HER2 targeted cancer therapy, numerous strategies including the blockage of receptor dimerization, inhibition of the tyrosine kinase activity, and interruption of the downstream signal pathway will be summarized. For the targeted drug delivery to HER2 positive tumor cells, various targeting ligands and their delivery systems will be described in details.
authors.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA.
authors.forename: Wanyi
authors.initials: W
authors.lastname: Tai
authors.forename: Rubi
authors.initials: R
authors.lastname: Mahato
authors.forename: Kun
authors.initials: K
authors.lastname: Cheng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases
references.citation: Ann Oncol. 2001;12 Suppl 1:S9-13
references.pmid: 11521729
references.citation: Nat Rev Mol Cell Biol. 2006 Jul;7(7):505-16
references.pmid: 16829981
references.citation: J Biol Chem. 2007 Apr 6;282(14):10432-40
references.pmid: 17283074
references.citation: Cancer Res. 2007 Mar 1;67(5):2178-86
references.pmid: 17332348
references.citation: Mol Pharm. 2006 Nov-Dec;3(6):726-36
references.pmid: 17140260
references.citation: Cancer Cell. 2004 Nov;6(5):427-8
references.pmid: 15542423
references.citation: Breast Cancer Res Treat. 2006 Aug;98(3):295-301
references.pmid: 16752078
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):15937-40
references.pmid: 12461170
references.citation: Cancer Cell. 2004 Sep;6(3):251-61
references.pmid: 15380516
references.citation: Cancer Immunol Immunother. 2007 Sep;56(9):1507-12
references.pmid: 17310381
references.citation: Mol Cell Biol. 1988 Apr;8(4):1831-4
references.pmid: 3260004
references.citation: Nat Med. 2000 Apr;6(4):443-6
references.pmid: 10742152
references.citation: Science. 1987 Jul 10;237(4811):178-82
references.pmid: 2885917
references.citation: Cancer Res. 2006 Feb 1;66(3):1630-9
references.pmid: 16452222
references.citation: Breast Cancer Res Treat. 2001 Mar;66(2):159-64
references.pmid: 11437102
references.citation: Cancer Res. 2007 Mar 15;67(6):2773-82
references.pmid: 17363599
references.citation: Mol Syst Biol. 2005;1:2005.0008
references.pmid: 16729043
references.citation: J Biol Chem. 1997 Nov 21;272(47):29482-6
references.pmid: 9368008
references.citation: Physiol Rev. 1999 Jul;79(3):703-61
references.pmid: 10390517
references.citation: Cancer Res. 2006 Apr 1;66(7):3764-72
references.pmid: 16585203
references.citation: Int J Cancer. 2004 Mar 1;108(6):922-9
references.pmid: 14712498
references.citation: Cancer Res. 2004 Feb 15;64(4):1460-7
references.pmid: 14973048
references.citation: Oncol Rep. 2002 Sep-Oct;9(5):915-28
references.pmid: 12168049
references.citation: Oncogene. 2007 May 28;26(25):3637-43
references.pmid: 17530017
references.citation: Semin Oncol. 2002 Jun;29(3 Suppl 11):29-37
references.pmid: 12138395
references.citation: Mol Cancer Res. 2008 Mar;6(3):446-57
references.pmid: 18337451
references.citation: Cancer Cell. 2002 Mar;1(2):117-23
references.pmid: 12086869
references.citation: Nat Clin Pract Oncol. 2006 May;3(5):269-80
references.pmid: 16683005
references.citation: J Natl Cancer Inst. 1993 Aug 4;85(15):1230-5
references.pmid: 8101229
references.citation: Biochem J. 1998 Aug 1;333 ( Pt 3):757-63
references.pmid: 9677338
references.citation: Br J Cancer. 2007 Feb 12;96(3):485-91
references.pmid: 17245339
references.citation: Int J Cancer. 2004 Jan 1;108(1):71-7
references.pmid: 14618618
references.citation: Clin Cancer Res. 2002 Apr;8(4):1172-81
references.pmid: 11948130
references.citation: Mol Pharm. 2009 May-Jun;6(3):649-50
references.pmid: 19485323
references.citation: Int J Biol Markers. 2003 Apr-Jun;18(2):152-5
references.pmid: 12841685
references.citation: J Biol Chem. 2002 Jun 21;277(25):22692-8
references.pmid: 11950845
references.citation: J Biol Chem. 2004 May 14;279(20):21343-8
references.pmid: 15004021
references.citation: J Virol. 2008 Jan;82(2):630-7
references.pmid: 17989185
references.citation: Cancer Res. 2001 Oct 1;61(19):7196-203
references.pmid: 11585755
references.citation: Nature. 2006 Jan 12;439(7073):168-74
references.pmid: 16273093
references.citation: Cancer Cell. 2004 Nov;6(5):517-27
references.pmid: 15542435
references.citation: DNA Cell Biol. 2005 Jun;24(6):350-8
references.pmid: 15941387
references.citation: Oncogene. 1994 Jul;9(7):1829-38
references.pmid: 7911565
references.citation: Nat Rev Mol Cell Biol. 2001 Feb;2(2):127-37
references.pmid: 11252954
references.citation: Cancer Res. 2004 Sep 15;64(18):6652-9
references.pmid: 15374980
references.citation: Mol Endocrinol. 2004 Jun;18(6):1396-410
references.pmid: 15056731
references.citation: Handb Exp Pharmacol. 2008;(185 Pt 2):145-63
references.pmid: 18626602
references.citation: Breast Cancer. 2008;15(1):65-72
references.pmid: 18224397
references.citation: Cancer Cell. 2004 Nov;6(5):459-69
references.pmid: 15542430
references.citation: Semin Oncol. 2002 Dec;29(6 Suppl 16):15-8
references.pmid: 12516034
references.citation: Clin Cancer Res. 2008 Jun 15;14(12):3840-9
references.pmid: 18559604
references.citation: Breast Cancer Res. 2006;8(1):R4
references.pmid: 16417653
references.citation: Gene Ther. 2006 Apr;13(7):646-51
references.pmid: 16341056
references.citation: Drugs. 2007;67(9):1329-41
references.pmid: 17547474
references.citation: Cancer Res. 2001 Mar 15;61(6):2420-3
references.pmid: 11289108
references.citation: Angiogenesis. 2004;7(1):59-68
references.pmid: 15302997
references.citation: J Biol Chem. 2004 Feb 6;279(6):4339-45
references.pmid: 14625284
references.citation: BioDrugs. 2007;21(2):69-77
references.pmid: 17402790
references.citation: Nat Clin Pract Oncol. 2008 Sep;5(9):512-20
references.pmid: 18594499
references.citation: J Clin Oncol. 2005 Apr 10;23(11):2534-43
references.pmid: 15699478
references.citation: Cancer Res. 2008 Nov 15;68(22):9280-90
references.pmid: 19010901
references.citation: Cancer Cell. 2004 Apr;5(4):317-28
references.pmid: 15093539
references.citation: Int J Oncol. 2000 Jan;16(1):65-73
references.pmid: 10601550
references.citation: Oncogene. 2005 Sep 15;24(41):6213-21
references.pmid: 16091755
references.citation: Mol Cancer Ther. 2009 Jan;8(1):185-93
references.pmid: 19139128
references.citation: J Natl Cancer Inst. 2000 Dec 6;92(23):1918-25
references.pmid: 11106683
references.citation: Biochim Biophys Acta. 2006 Apr;1758(4):429-42
references.pmid: 16678786
references.citation: Br J Cancer. 2001 May 4;84(9):1252-7
references.pmid: 11336478
references.citation: Ann Surg Oncol. 2010 Jan;17(1):14-7
references.pmid: 19841980
references.citation: Mol Pharm. 2010 Apr 5;7(2):543-56
references.pmid: 20047302
references.citation: Cancer Res. 2003 Jun 15;63(12):3257-62
references.pmid: 12810656
references.citation: Ann Oncol. 2001;12 Suppl 1:S3-8
references.pmid: 11521719
references.citation: Surgery. 1999 Aug;126(2):413-21
references.pmid: 10455915
references.citation: Biochemistry. 2000 May 30;39(21):6572-80
references.pmid: 10828974
references.citation: Cancer. 1996 Jan 1;77(1):113-20
references.pmid: 8630916
references.citation: Int J Gynecol Cancer. 2007 Jul-Aug;17(4):798-807
references.pmid: 17309668
references.citation: J Natl Cancer Inst. 1986 Nov;77(5):1047-52
references.pmid: 3464796
references.citation: J Cell Biol. 2003 Jun 23;161(6):1191-203
references.pmid: 12810698
references.citation: J Surg Res. 1998 Jun;77(1):85-90
references.pmid: 9698539
references.citation: Endocr Relat Cancer. 2005 Jul;12 Suppl 1:S17-27
references.pmid: 16113093
references.citation: Mol Cell Biol. 2005 Dec;25(24):11005-18
references.pmid: 16314522
references.citation: BioDrugs. 2007;21(4):209-14
references.pmid: 17628118
references.citation: Cancer Cell. 2002 Aug;2(2):127-37
references.pmid: 12204533
references.citation: Mol Cancer Res. 2003 Mar;1(5):385-92
references.pmid: 12651911
references.citation: Nature. 2001 Mar 1;410(6824):24-5
references.pmid: 11242022
references.citation: Cancer. 2003 Oct 1;98(7):1377-85
references.pmid: 14508823
references.citation: Proc Natl Acad Sci U S A. 1999 May 11;96(10):5458-63
references.pmid: 10318905
references.citation: Breast Cancer Res. 2003;5(6):R217-22
references.pmid: 14580257
references.citation: J Med Chem. 2002 Sep 12;45(19):4336-43
references.pmid: 12213074
references.citation: J Clin Oncol. 2003 Jan 15;21(2):283-90
references.pmid: 12525520
references.citation: Cell Mol Life Sci. 2008 Nov;65(23):3756-88
references.pmid: 18726070
references.citation: Eur J Cancer. 2007 Feb;43(3):481-9
references.pmid: 17208435
references.citation: J Cell Biol. 2004 Nov 8;167(3):469-78
references.pmid: 15534001
references.citation: ChemMedChem. 2008 Dec;3(12):1839-43
references.pmid: 19012296
references.citation: Oncogene. 2002 Sep 12;21(41):6255-63
references.pmid: 12214266
references.citation: Cancer Res. 2009 Dec 15;69(24):9330-6
references.pmid: 19934333
references.citation: Oncogene. 1996 Sep 5;13(5):883-9
references.pmid: 8806677
references.citation: J Biomed Sci. 2003 May-Jun;10(3):337-44
references.pmid: 12711861
references.citation: Cancer Res. 2007 Apr 1;67(7):3337-44
references.pmid: 17409443
references.citation: Cancer Gene Ther. 2001 Aug;8(8):555-65
references.pmid: 11571533
references.citation: Cancer Res. 1995 Aug 1;55(15):3331-8
references.pmid: 7614468
references.citation: Clin Adv Hematol Oncol. 2006 Oct;4(10 Suppl 21):1-10; quiz 11-2
references.pmid: 17139244
references.citation: Nat Biotechnol. 2005 Jun;23(6):709-17
references.pmid: 15908939
references.citation: Mol Cancer Ther. 2007 Jan;6(1):93-100
references.pmid: 17237269
references.citation: Cancer Res. 2004 Apr 1;64(7):2343-6
references.pmid: 15059883
references.citation: Clin Cancer Res. 2002 Apr;8(4):955-6
references.pmid: 11948099
references.citation: Semin Oncol. 2001 Aug;28(4 Suppl 15):71-6
references.pmid: 11685733
references.citation: Mol Cancer Ther. 2005 Jun;4(6):956-67
references.pmid: 15956253
references.citation: Neoplasia. 2004 Nov-Dec;6(6):786-95
references.pmid: 15720805
references.citation: Cancer Res. 2007 Jan 1;67(1):269-75
references.pmid: 17210707
references.citation: Biophys J. 2009 Mar 18;96(6):2321-34
references.pmid: 19289058
references.citation: Nat Cell Biol. 2001 Sep;3(9):802-8
references.pmid: 11533659
references.citation: Prostate. 2004 Sep 1;60(4):332-7
references.pmid: 15264245
references.citation: Cancer Res. 2005 Apr 15;65(8):3404-9
references.pmid: 15833875
references.citation: Clin Cancer Res. 2004 Mar 1;10(5):1706-16
references.pmid: 15014023
references.citation: Nature. 2002 Mar 21;416(6878):279-80
references.pmid: 11907566
references.citation: Cancer Res. 1991 Feb 1;51(3):1034-8
references.pmid: 1670998
references.citation: FASEB J. 2003 Feb;17(2):256-8
references.pmid: 12490548
references.citation: Curr Hematol Rep. 2004 Jul;3(4):267-73
references.pmid: 15217556
references.citation: Nat Med. 1999 Mar;5(3):280-5
references.pmid: 10086382
references.citation: Cancer Res. 2005 Feb 1;65(3):967-71
references.pmid: 15705897
references.citation: N Engl J Med. 2005 Oct 20;353(16):1659-72
references.pmid: 16236737
references.citation: J Natl Cancer Inst. 2000 Dec 6;92(23):1866-8
references.pmid: 11106669
references.citation: Oncogene. 1995 Jun 15;10(12):2435-46
references.pmid: 7784095
references.citation: Semin Oncol. 2003 Oct;30(5 Suppl 16):54-64
references.pmid: 14613027
references.citation: Cancer Gene Ther. 2005 Jan;12(1):84-9
references.pmid: 15472715
references.citation: Eur J Cancer. 2000 Apr;36(6):780-6
references.pmid: 10762752
references.citation: J Biol Chem. 2002 Feb 15;277(7):4704-12
references.pmid: 11741943
references.citation: Expert Opin Biol Ther. 2010 Feb;10(2):243-50
references.pmid: 20001562
references.citation: Cancer. 1993 Dec 1;72(11):3179-84
references.pmid: 7902202
references.citation: Cancer Res. 2005 Mar 1;65(5):1783-91
references.pmid: 15753375
references.citation: Nature. 2001 Mar 1;410(6824):50-6
references.pmid: 11242036
references.citation: Cancer. 2003 Nov 15;98(10):2125-32
references.pmid: 14601081
references.citation: Cancer Res. 2000 Feb 1;60(3):560-5
references.pmid: 10676637
references.citation: Nat Biotechnol. 2000 Feb;18(2):194-8
references.pmid: 10657127
references.citation: Protein Eng Des Sel. 2004 May;17(5):455-62
references.pmid: 15208403
references.citation: Mol Endocrinol. 2001 Aug;15(8):1344-59
references.pmid: 11463858
references.citation: Cancer Res. 2005 Aug 1;65(15):6891-900
references.pmid: 16061673
references.citation: N Engl J Med. 2005 Oct 20;353(16):1673-84
references.pmid: 16236738
references.citation: Mol Cell. 2003 Feb;11(2):495-505
references.pmid: 12620236
references.citation: Cancer Biother Radiopharm. 2005 Jun;20(3):239-48
references.pmid: 15989469
references.citation: Eur J Cancer. 2004 Jan;40(1):33-42
references.pmid: 14687787
references.citation: Histopathology. 2000 Dec;37(6):536-45
references.pmid: 11122436
references.citation: Cell Prolif. 2007 Aug;40(4):488-507
references.pmid: 17635517
references.citation: J Clin Oncol. 2009 Dec 10;27(35):6052-69
references.pmid: 19901123
references.citation: Clin Med Res. 2009 Jun;7(1-2):4-13
references.pmid: 19574486
references.citation: Clin Breast Cancer. 2008 Oct;8(5):392-401
references.pmid: 18952552