Vascular endothelial growth factor receptor-2 in breast cancer.
Investigations over the last decade have established the essential role of growth factors and their receptors during angiogenesis and carcinogenesis. The vascular endothelial growth factor receptor (VEGFR) family in mammals contains three members, VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1) and VEGFR-3 (Flt-4), which are transmembrane tyrosine kinase receptors that regulate the formation of blood and lymphatic vessels. In the early 1990s, the above VEGFR was structurally characterized by cDNA cloning. Among these three receptors, VEGFR-2 is generally recognized to have a principal role in mediating VEGF-induced responses. VEGFR-2 is considered as the earliest marker for endothelial cell development. Importantly, VEGFR-2 directly regulates tumor angiogenesis. Therefore, several inhibitors of VEGFR-2 have been developed and many of them are now in clinical trials. In addition to targeting endothelial cells, the VEGF/VEGFR-2 system works as an essential autocrine/paracrine process for cancer cell proliferation and survival. Recent studies mark the continuous and increased interest in this related, but distinct, function of VEGF/VEGFR-2 in cancer cells: the autocrine/paracrine loop. Several mechanisms regulate VEGFR-2 levels and modulate its role in tumor angiogenesis and physiologic functions, i.e.: cellular localization/trafficking, regulation of cis-elements of promoter, epigenetic regulation and signaling from Notch, cytokines/growth factors and estrogen, etc. In this review, we will focus on updated information regarding VEGFR-2 research with respect to the molecular mechanisms of VEGFR-2 regulation in human breast cancer. Investigations in the activation, function, and regulation of VEGFR-2 in breast cancer will allow the development of new pharmacological strategies aimed at directly targeting cancer cell proliferation and survival.
Guo
Shanchun
S
Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA.
Colbert
Laronna S
LS
Fuller
Miles
M
Zhang
Yuanyuan
Y
Gonzalez-Perez
Ruben R
RR
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000209:etiology*; D002470:Cell Survival; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*
D020533:Angiogenesis Inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2
J Biol Chem. 2009 Mar 6;284(10):6038-42
19112107
EMBO J. 1999 Jan 15;18(2):363-74
9889193
Endocr Relat Cancer. 2006 Sep;13(3):905-19
16954439
J Vasc Res. 2009;46(2):103-8
18617751
Biochem Soc Trans. 2009 Dec;37(Pt 6):1184-8
19909243
Cell. 2007 Feb 23;128(4):693-705
17320507
Clin Cancer Res. 2004 May 15;10(10):3365-70
15161690
Breast Cancer Res Treat. 2005 Jan;89(2):135-43
15692755
J Biol Chem. 1997 Mar 7;272(10):6093-6
9102398
Cancer Res. 1997 Sep 1;57(17):3852-9
9288799
FEBS Lett. 2003 Jan 30;535(1-3):87-93
12560084
Nat Rev Genet. 2002 Jun;3(6):415-28
12042769
Expert Opin Ther Targets. 2010 Apr;14(4):443-51
20230196
Mol Cell Endocrinol. 2002 Feb 25;188(1-2):219-26
11911959
Int J Cancer. 2009 Mar 1;124(5):1045-53
19058181
Cancer Biol Ther. 2009 Dec;8(23):2286-96
19923922
Nature. 1993 Apr 29;362(6423):841-4
7683111
J Clin Oncol. 2006 Feb 10;24(5):769-77
16391297
Oncol Rep. 2009 Dec;22(6):1473-8
19885601
Cancer Gene Ther. 2008 Oct;15(10):667-75
18566614
Biophys Chem. 2007 Jul;128(2-3):125-39
17442480
J Oral Sci. 2009 Dec;51(4):551-7
20032607
Oncogene. 2008 Sep 1;27(38):5099-109
18758478
Biochem Biophys Res Commun. 2009 Apr 24;382(1):124-8
19265684
Angiogenesis. 2003;6(4):295-301
15166498
Cancer Res. 2006 Feb 1;66(3):1517-25
16452208
Cancer Res. 1997 Dec 1;57(23):5421-5
9393770
Proc Soc Exp Biol Med. 1997 Oct;216(1):28-43
9316608
Oncogene. 1997 May 1;14(17):2079-89
9160888
J Clin Oncol. 2008 Apr 10;26(11):1871-8
18398152
N Engl J Med. 2004 Jun 3;350(23):2335-42
15175435
Biochem Biophys Res Commun. 1997 Sep 18;238(2):648-52
9299568
Breast. 2007 Dec;16 Suppl 2:S17-9
17707641
IUBMB Life. 2001 Jul;52(1-2):61-6
11795595
Science. 2001 Aug 10;293(5532):1074-80
11498575
J Cell Mol Med. 2000 Oct-Dec;4(4):262-269
12067460
FASEB J. 2009 Oct;23(10):3368-76
19528255
Biochem J. 2004 Nov 15;384(Pt 1):79-85
15270719
Cancer Sci. 2003 Sep;94(9):751-6
12967471
Physiol Rev. 2002 Jul;82(3):673-700
12087132
Proc Nutr Soc. 2008 May;67(2):128-45
18412987
Biochim Biophys Acta. 2009 Dec;1796(2):194-200
19559756
BMC Cancer. 2008 Oct 22;8:305
18945363
J Surg Res. 2008 Sep;149(1):9-14
18262553
Nat Rev Mol Cell Biol. 2006 May;7(5):359-71
16633338
Breast Cancer Res. 2009;11(3):R36
19531256
J Biol Chem. 1998 Jul 24;273(30):19294-303
9668119
J Clin Oncol. 2005 Feb 10;23(5):1011-27
15585754
J Biol Chem. 1998 Aug 21;273(34):22128-35
9705358
FASEB J. 2000 Dec;14(15):2532-9
11099472
Cardiovasc Res. 2010 May 1;86(2):226-35
20154066
J Biol Chem. 1998 Nov 20;273(47):31273-82
9813035
Cancer Res. 1995 Sep 15;55(18):3964-8
7664263
Mol Biol Cell. 2005 Apr;16(4):2106-18
15673613
J Biol Chem. 1994 Oct 14;269(41):25646-54
7929268
J Anim Sci. 2004 Mar;82(3):925-34
15032451
Genes Dev. 2007 Oct 15;21(20):2511-24
17938237
Breast Cancer Res Treat. 2003 Dec;82(3):147-54
14703061
Cancer Lett. 2009 Aug 8;280(2):145-53
19111391
Cell Death Differ. 2010 Mar;17(3):499-512
19834490
J Cell Biochem. 2008 Nov 1;105(4):956-64
18821585
Mol Ther. 2006 May;13(5):947-55
16455304
J Clin Oncol. 2007 Jul 20;25(21):3045-54
17634482
J Biol Chem. 1999 Jan 29;274(5):3207-14
9915861
Int J Cancer. 2000 Jan 1;85(1):27-34
10585578
Blood. 1997 Jul 1;90(1):111-25
9207445
J Biol Chem. 1997 Jun 13;272(24):15442-51
9182576
Curr Top Microbiol Immunol. 1999;237:1-30
9893343
Invest New Drugs. 2004 Nov;22(4):459-66
15292716
J Biol Chem. 2005 Mar 18;280(11):9904-12
15637071
Angiogenesis. 2009;12(2):177-85
19267251
Sci STKE. 2005 Jun 14;2005(288):pe28
15956360
Bioorg Med Chem Lett. 2009 Dec 1;19(23):6552-6
19854051
Ann N Y Acad Sci. 2009 Feb;1155:132-40
19250200
Cancer Res. 2008 Jul 1;68(13):5273-81
18593928
Traffic. 2010 Jan;11(1):161-74
19883397
Cancer Res. 1998 Aug 1;58(15):3209-14
9699643
Circ Res. 2001 Mar 2;88(4):E38-47
11230116
Nature. 2002 Jan 17;415(6869):339-43
11797013
Mymensingh Med J. 2009 Jan;18(1 Suppl):S140-144
19436260
J Biol Chem. 2003 Aug 1;278(31):28668-76
12734209
Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10857-62
11553814
Nat Med. 2003 Jul;9(7):936-43
12796773
Mol Endocrinol. 2004 Sep;18(9):2333-43
15192074
J Mol Med (Berl). 2007 Nov;85(11):1175-86
17589818
J Biol Chem. 1997 Mar 28;272(13):8410-6
9079666
Bioessays. 1998 Aug;20(8):615-26
9780836
Oncogene. 2000 Jan 13;19(2):223-31
10645000
Carcinogenesis. 2008 May;29(5):1077-82
18359762
Cancer Res. 1999 Jan 1;59(1):99-106
9892193
Biochem Soc Trans. 2003 Dec;31(Pt 6):1171-7
14641020
Invest New Drugs. 2007 Apr;25(2):165-72
16983506
Cancer Res. 2003 Nov 1;63(21):7301-9
14612527
Oncogene. 1993 Jan;8(1):11-8
8423988
Nature. 1994 Feb 10;367(6463):576-9
8107827
Exp Mol Med. 2005 Aug 31;37(4):353-64
16155412
Angiogenesis. 2005;8(4):289-96
16328158
J Steroid Biochem Mol Biol. 2006 Dec;102(1-5):89-96
17113977
Cancer Sci. 2003 Jun;94(6):536-9
12824880
Br J Ophthalmol. 2008 Mar;92(3):356-60
18303156
Nat Med. 2001 Feb;7(2):199-205
11175851
Curr Biol. 1997 Feb 1;7(2):R82-4
9081669
Eur J Clin Invest. 2007 Nov;37(11):878-86
17883421
Cancer Res. 2009 Jun 1;69(11):4716-23
19435899
Oncogene. 1990 Apr;5(4):519-24
2158038
Cell. 1993 Mar 26;72(6):835-46
7681362
J Biol Chem. 2009 Aug 28;284(35):23217-24
19570985
EMBO J. 1996 Apr 1;15(7):1751
8612600
BMC Cancer. 2009 Jun 29;9:212
19563658
Mol Cancer Ther. 2006 Jul;5(7):1744-53
16891460
Exp Biol Med (Maywood). 2004 Feb;229(2):182-93
14734797
Lung Cancer. 2004 Oct;46(1):11-9
15364128
Cancer Res. 2009 Jul 15;69(14):5893-900
19567671
J Clin Invest. 1996 Jul 15;98(2):490-6
8755661
Science. 1998 Sep 11;281(5383):1683-6
9733517
Vascul Pharmacol. 2002 Feb;38(2):89-98
12379955
J Biol Chem. 2001 May 25;276(21):17686-92
11278468
J Biol Chem. 1997 Sep 19;272(38):23659-67
9295307
J Biol Chem. 2003 Oct 17;278(42):40973-9
12881528
Breast Cancer Res Treat. 2003 Feb;77(3):205-15
12602920
Nature. 1994 Apr 14;368(6472):643-8
8145851
Biochem Biophys Res Commun. 2006 Jun 23;345(1):292-301
16678129
Exp Dermatol. 2009 Oct;18(10):863-9
19469899
Anticancer Res. 2007 Mar-Apr;27(2):889-94
17465216
J Urol. 2006 Apr;175(4):1245-52
16515971
Oncogene. 1991 Sep;6(9):1677-83
1656371
Int J Mol Med. 2000 Apr;5(4):421-6
10719061
N Engl J Med. 2003 Jul 31;349(5):427-34
12890841
Clin Cancer Res. 2005 Sep 1;11(17):6240-6
16144927
J Natl Cancer Inst. 2002 Nov 20;94(22):1704-11
12441326
Gynecol Oncol. 2004 Sep;94(3):630-5
15350351
Microvasc Res. 2002 Nov;64(3):372-83
12453432
Cancer Res. 1992 Oct 15;52(20):5738-43
1327515
Breast Cancer Res. 2008;10(6):R97
19025652
Development. 1997 May;124(10):2039-48
9169850
Oncogene. 2004 Jan 15;23(2):612-6
14724590
Nature. 2000 Sep 14;407(6801):242-8
11001067
Med Res Rev. 2008 Mar;28(2):185-200
17457812
Clin Colorectal Cancer. 2009 Jan;8(1):59-60
19203899
J Steroid Biochem Mol Biol. 2008 Feb;108(3-5):261-6
17945482
Cancer Res. 2001 Aug 1;61(15):5736-40
11479209
Int J Cancer. 2006 Oct 1;119(7):1519-29
16671089
Semin Cancer Biol. 2004 Apr;14(2):115-22
15018895
Int J Biochem Cell Biol. 2001 Apr;33(4):315-24
11312102
Cancer Res. 2007 Jan 15;67(2):593-9
17234768
Cell. 2004 Sep 17;118(6):781-94
15369676
Science. 1999 Apr 30;284(5415):770-6
10221902
Biochemistry. 2009 Jul 28;48(29):7019-31
19526984
Nat Med. 2003 Jun;9(6):669-76
12778165
Trends Cell Biol. 2001 Jun;11(6):266-73
11356363
Cancer Res. 2004 Sep 15;64(18):6626-34
15374977
Radiat Res. 2009 Nov;172(5):584-91
19883226
Int J Cancer. 1989 May 15;43(5):922-5
2497075
Endocrinology. 2006 Jul;147(7):3285-95
16574784
Cancer Res. 2000 Jan 15;60(2):203-12
10667560
Breast Cancer Res. 2007;9(6):216
18190723
Circ Res. 1996 Aug;79(2):277-85
8756005
Eur J Cancer. 2004 May;40(7):1066-72
15093584
Nature. 1995 Jul 6;376(6535):62-6
7596435
Breast Cancer Res Treat. 2009 Jul;116(1):31-8
19101790
Nature. 2000 Jan 6;403(6765):41-5
10638745
J Biol Chem. 1995 Sep 29;270(39):23111-8
7559454
Cell. 2009 Jun 12;137(6):1124-35
19524514
Invest Ophthalmol Vis Sci. 1999 Aug;40(9):2122-9
10440269
Cancer Res. 2003 Sep 15;63(18):5978-91
14522925
Biochem Biophys Res Commun. 1992 Jul 31;186(2):706-14
1323289
Mol Cancer Res. 2008 Oct;6(10):1630-8
18922978
Nat Med. 1996 May;2(5):585-9
8616721
Mol Endocrinol. 2008 Feb;22(2):388-402
18006642
Curr Opin Cell Biol. 2009 Apr;21(2):154-65
19230644
Clin Cancer Res. 2003 Apr;9(4):1323-32
12684400
J Biol Chem. 1998 Nov 20;273(47):31283-8
9813036
Nature. 1997 Apr 17;386(6626):671-4
9109485
Mol Cancer Res. 2006 Dec;4(12):927-34
17189383
Jpn J Cancer Res. 1997 Sep;88(9):867-76
9369935
J Biol Chem. 2009 Dec 4;284(49):33966-81
19837659
Clin Cancer Res. 2006 Mar 1;12(5):1630-8
16533791
J Biol Chem. 1997 Apr 18;272(16):10382-8
9099677
BMC Cancer. 2008 Nov 27;8:352
19038046
Hum Pathol. 2002 Sep;33(9):863-70
12378509
Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):548-53
9435229
Genes Nutr. 2009 Mar;4(1):69-72
19224264
J Pathol. 2010 Feb;220(3):370-81
19967723
Cancer. 2009 Apr 15;115(8):1701-12
19197998
Eur J Immunol. 2009 Sep;39(9):2556-70
19662631
Dev Cell. 2009 Feb;16(2):196-208
19217422
Angiogenesis. 2005;8(3):197-204
16328160
Cell. 1999 Jul 23;98(2):147-57
10428027
FASEB J. 2003 Feb;17(2):262-4
12490545
Blood. 2008 May 15;111(10):4997-5007
18337563
Curr Oncol Rep. 2001 Mar;3(2):141-6
11177746
Biochem Biophys Res Commun. 1992 Sep 30;187(3):1579-86
1417831
Blood. 2006 Feb 1;107(3):931-9
16219802
J Biol Chem. 2005 Sep 9;280(36):31508-15
16027124
Blood. 2006 Apr 15;107(8):3153-60
16352813
Int J Cancer. 2000 Apr 15;86(2):174-81
10738243
Nature. 2005 Sep 15;437(7057):426-31
16163360
J Biochem Mol Biol. 2006 Sep 30;39(5):469-78
17002866
Cancer Res. 2007 Nov 15;67(22):10759-65
18006819
Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9026-30
1717995
Immunol Lett. 2009 Sep 22;126(1-2):60-6
19665480
J Mammary Gland Biol Neoplasia. 2006 Jan;11(1):41-52
16947085
Nature. 2004 Sep 23;431(7007):461-6
15329734
Biochim Biophys Acta. 2008 Sep;1783(9):1654-62
18472010
Int J Cancer. 2008 Dec 15;123(12):2782-90
18798554
J Biol Chem. 1994 Oct 28;269(43):26988-95
7929439
EMBO J. 2005 Jul 6;24(13):2342-53
15962004
Front Biosci. 2006 Jan 01;11:818-29
16146773
Int J Cancer. 1999 Jun 21;84(3):293-8
10371349
Int J Cancer. 2010 Jul 1;127(1):55-66
19876927
EMBO J. 1996 Sep 16;15(18):4919-27
8890165
Steroids. 2004 Aug;69(8-9):537-42
15288766
Anticancer Res. 1999 Sep-Oct;19(5B):4203-14
10628376
Oncogene. 2005 Jun 23;24(27):4370-9
15806151
J Biol Chem. 2000 May 12;275(19):14321-30
10799512
J Clin Oncol. 2005 Feb 1;23(4):792-9
15681523
Biochem Soc Trans. 2009 Dec;37(Pt 6):1193-7
19909245
Nature. 1995 Jul 6;376(6535):66-70
7596436
Hum Pathol. 1995 Jan;26(1):86-91
7821921
Oncol Rep. 2008 Oct;20(4):845-50
18813825
Nat Rev Mol Cell Biol. 2006 Sep;7(9):678-89
16921404
Mol Vis. 2004 Dec 06;10:923-32
15616479
Epigenetics. 2009 Jul 1;4(5):313-21
19633424
J Biol Chem. 2006 Sep 8;281(36):26320-8
16825198
Exp Cell Res. 2006 Mar 10;312(5):549-60
16336962