NF-kappaB activation in inflammatory breast cancer is associated with oestrogen receptor downregulation, secondary to EGFR and/or ErbB2 overexpression and MAPK hyperactivation.
Activation of NF-kappaB in inflammatory breast cancer (IBC) is associated with loss of estrogen receptor (ER) expression, indicating a potential crosstalk between NF-kappaB and ER. In this study, we examined the activation of NF-kappaB in IBC and non-IBC with respect to ER and EGFR and/or ErbB2 expression and MAPK hyperactivation. A qRT-PCR based ER signature was evaluated in tumours with and without transcriptionally active NF-kappaB, as well as correlated with the expression of eight NF-kappaB target genes. Using a combined ER/NF-kappaB signature, hierarchical clustering was executed. Hyperactivation of MAPK was investigated using a recently described MAPK signature (Creighton et al, 2006), and was linked to tumour phenotype, ER and EGFR and/or ErbB2 overexpression. The expression of most ER-modulated genes was significantly elevated in breast tumours without transcriptionally active NF-kappaB. In addition, the expression of most ER-modulated genes was significantly anticorrelated with the expression of most NF-kappaB target genes, indicating an inverse correlation between ER and NF-kappaB activation. Clustering using the combined ER and NF-kappaB signature revealed one cluster mainly characterised by low NF-kappaB target gene expression and a second one with elevated NF-kappaB target gene expression. The first cluster was mainly characterised by non-IBC specimens and IHC ER+ breast tumours (13 out of 18 and 15 out of 18 respectively), whereas the second cluster was mainly characterised by IBC specimens and IHC ER- breast tumours (12 out of 19 and 15 out of 19 respectively) (Pearson chi(2), P<0.0001 and P<0.0001 respectively). Hyperactivation of MAPK was associated with both ER status and tumour phenotype by unsupervised hierarchical clustering using the MAPK signature and was significantly reflected by overexpression of EGFR and/or ErbB2. NF-kappaB activation is linked to loss of ER expression and activation in IBC and in breast cancer in general. The inverse correlation between NF-kappaB activation and ER activation is due to EGFR and/or ErbB2 overexpression, resulting in NF-kappaB activation and ER downregulation.
Van Laere
S J
SJ
Translational Cancer Research Group, Lab Pathology University of Antwerp, Universiteitsplein 1 and Oncology Center, General Hospital Sint-Augustinus, Oosterveldlaan 24, Wilrijk B2610, Belgium.
Van der Auwera
I
I
Van den Eynden
G G
GG
van Dam
P
P
Van Marck
E A
EA
Vermeulen
P B
PB
Dirix
L Y
LY
D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016000:Cluster Analysis; D015536:Down-Regulation; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; C512478:EGFR protein, human; C508053:ERBB2 protein, human
Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10386-91
11517301
Nature. 2000 Aug 17;406(6797):747-52
10963602
Breast Cancer Res. 2005;7(2):52-8
15743511
Int J Biochem Cell Biol. 2005 May;37(5):1130-44
15743683
J Cell Mol Med. 2005 Jan-Mar;9(1):208-21
15784178
BMC Genomics. 2005;6:37
15762987
Breast Cancer Res Treat. 2005 Oct;93(3):237-46
16172796
Breast Cancer Res Treat. 2006 Feb;95(3):243-55
16261404
Cancer Res. 2006 Apr 1;66(7):3903-11
16585219
Clin Cancer Res. 2006 Jun 1;12(11 Pt 1):3249-56
16740744
AAOHN J. 2006 Oct;54(10):445-51; quiz 452-3
17059162
Methods. 2001 Dec;25(4):402-8
11846609
Lancet Oncol. 2001 Mar;2(3):133-40
11902563
Clin Exp Metastasis. 2002;19(4):301-11
12090470
J Clin Oncol. 2002 Sep 1;20(17):3628-36
12202663
Br J Cancer. 2003 Mar 10;88(5):718-25
12618881
Breast Cancer Res. 2003;5(3):174-9
12793901
Mol Biol Cell. 2003 Jul;14(7):3041-54
12857884
Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10393-8
12917485
Mol Cell Biol. 2003 Oct;23(19):6887-900
12972607
Breast Cancer Res. 2004;6(1):R110-5
14696649
Breast Cancer Res Treat. 2004 May;85(1):13-22
15039594
Proc Natl Acad Sci U S A. 2000 Jul 18;97(15):8542-7
10900013
Clin Cancer Res. 2004 Dec 1;10(23):7965-71
15585631
Neoplasia. 2000 Sep-Oct;2(5):418-25
11191108
Breast Cancer Res. 2000;2(6):423-9
11250736
Mol Endocrinol. 2001 Aug;15(8):1344-59
11463858
Cancer Cell. 2004 Mar;5(3):207-13
15050912
Mol Endocrinol. 2004 Jun;18(6):1396-410
15056731
Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10137-42
15220474
Oncogene. 2004 Aug 12;23(36):6105-14
15208657
Clin Cancer Res. 2004 Aug 15;10(16):5367-74
15328174
J Clin Oncol. 2004 Oct 15;22(20):4067-74
15483018
Mol Cell Biol. 1995 Sep;15(9):4971-9
7651415
Mol Cell Biol. 1997 Jul;17(7):3629-39
9199297
Clin Cancer Res. 1999 Sep;5(9):2511-9
10499627
Trends Endocrinol Metab. 2005 Mar;16(2):46-52
15734144