Identification of a Stat3-dependent transcription regulatory network involved in metastatic progression.
High levels of activated Stat3 are often found in human breast cancers and can correlate with poor patient outcome. We employed an activated ErbB2 mouse model of breast cancer to investigate the in vivo role of Stat3 in mammary tumor progression and found that Stat3 does not alter mammary tumor initiation but dramatically affects metastatic progression. Four-fold fewer animals exhibited lung metastases in the absence of Stat3 and a 12-fold reduction in the number of lung lesions was observed in animals bearing Stat3-null tumors when compared with the wild-type cohort. The decreased malignancy in Stat3-deficient tumors is attributed to a reduction in both angiogenic and inflammatory responses associated with a Stat3-dependent transcriptional cascade involving CCAAT/enhancer binding protein delta.
Ranger
Jill J
JJ
Goodman Cancer Centre, McGill University, Montreal, Quebec, Canada.
Levy
David E
DE
Shahalizadeh
Solmaz
S
Hallett
Michael
M
Muller
William J
WJ
D000818:Animals; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic
D051743:CCAAT-Enhancer-Binding Protein-delta; D018719:Erb-b2 Receptor Tyrosine Kinases; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C524056:Erbb2 protein, mouse
Am J Pathol. 2008 Jun;172(6):1717-28
18483213
Cell. 1999 Aug 6;98(3):295-303
10458605
Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):2846-51
10077599
Cell Res. 2008 Feb;18(2):254-67
18227858
Mol Cell Biol. 2001 Mar;21(5):1621-32
11238899
Oncogene. 2003 Mar 13;22(10):1517-27
12629515
Exp Dermatol. 2006 Apr;15(4):291-9
16512876
Mol Cell Biol. 1998 Apr;18(4):2108-17
9528783
J Clin Pathol. 2007 Jun;60(6):642-8
16901975
Methods. 2003 Dec;31(4):265-73
14597310
Oncogene. 2001 Nov 29;20(55):7925-34
11753675
Cancer Cell. 2004 Aug;6(2):159-70
15324699
Mol Endocrinol. 2006 Mar;20(3):675-85
16293640
World J Gastroenterol. 2004 Jun 1;10(11):1569-73
15162527
Cell Growth Differ. 2002 Aug;13(8):355-62
12193474
Cancer Lett. 2007 Jun 28;251(2):199-210
17129668
Brief Bioinform. 2001 Dec;2(4):341-9
11808746
Development. 2005 Nov;132(21):4675-85
16192306
J Clin Immunol. 1999 Jul;19(4):203-14
10471974
J Cell Biochem. 2007 Dec 1;102(5):1256-70
17471507
EMBO J. 2008 Mar 19;27(6):910-20
18273058
Mol Cell Biol. 1994 Jun;14(6):4324-32
8196668
Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4227-32
10760290
Mol Cell Biol. 1998 May;18(5):2553-8
9566875
Biostatistics. 2003 Apr;4(2):249-64
12925520
J Biol Chem. 2001 Nov 30;276(48):45443-55
11579100
J Biol Chem. 2002 Oct 11;277(41):38486-93
11940572
Int J Cancer. 2006 Jun 15;118(12):2943-7
16425286
J Anim Sci. 2009 Apr;87(13 Suppl):35-42
18849387
Oncogene. 2005 Aug 25;24(36):5552-60
16007214
Oncogene. 2002 Mar 27;21(13):2000-8
11960372
Cell Growth Differ. 1997 Dec;8(12):1267-76
9419415
Am J Pathol. 2006 Feb;168(2):608-20
16436674
Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10602-7
15249664
Oncogene. 2004 Apr 29;23(20):3550-60
15116091
Oncogene. 2002 Jan 10;21(2):217-26
11803465
Cancer Res. 2006 Dec 1;66(23):11238-46
17114237
Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):151-6
19109434
Biochem Biophys Res Commun. 2005 Sep 23;335(2):292-9
16081048
Clin Cancer Res. 2006 Jan 1;12(1):20-8
16397019
Nat Rev Cancer. 2004 Feb;4(2):97-105
14964307
Bioinformatics. 2006 Nov 15;22(22):2825-7
16982708
J Mammary Gland Biol Neoplasia. 2009 Jun;14(2):121-9
19424782
Oncology. 2005;69 Suppl 3:4-10
16301830
Endocrinology. 2002 Sep;143(9):3641-50
12193580
Breast Cancer Res. 2004;6(2):R75-91
14979920
Bioinformatics. 2005 Apr 15;21(8):1745-6
15572471