PROGNOSTIC AND THERAPEUTIC ROLE OF NUCLEAR FACTORkappa B (NF-κB) IN BREAST CANCER
Abstract
Nuclear Factor- kappa B (NF-κB) is an essential transcription factor that not only modulates cellularresponses to stress but also plays a pivotal role in inflammation, immunity, cell cycle growth andsurvival. NF-κB-regulated genes have been documented to be involved in cellular proliferation andinvasion along with tumour related angiogenesis and lymphangiogenesis. Dysregulation of NF-κBassociated pathways are seen in multiple malignancies. Its constitutive activation in the clinicallyaggressive and prognostically poor ER-negative, Her2-neu positive and inflammatory breast cancercould formulate the basis for its evolution as a potential prognostic and therapeutic target.Keywords: Nuclear Factor kappa B, NF-κB, Breast Cancer, ER-negativeReferences
Baldwin AS Jr. The NF-κB, IkB proteins: new discoveries and
insights. Annu Rev Immunol 1996;14:649–83.
Finco TS, Baldwin AS. Mechanistic aspects of NF-κB regulation:
the emerging role of phosphorylation and proteolysis. Immunity
;3:263–72.
Barnes PJ, Karin M. Nuclear factor-kB—A pivotal transcription
factor in chronic inflammatory diseases. New Engl J Med
;366:1066–71.
Hayden M, Ghosh S: Signaling to NF-κB. Genes & Development
;18:2195–224.
Bonizzi G, Karin M. The two NF-κB activation pathways and
their role in innate and adaptive immunity. Trends in Immunology
;25(6):280–8.
Pasparakis M, Luedde T, Schmidt-Supprian M: Dissection of the
NF-κB signalling cascade in transgenic and knockout mice. Cell
Death & Differentiation 2006;13:861–72.
Pahl HL. Activators and target genes of Rel/NF-κB transcription
factors. Oncogene 1999;18(49):6853–66.
Ghosh S, May M, Kopp E. NF-κB and rel proteins:
Evolutionarily conserved mediators of immune responses. Ann
Rev Immunol 1998;16:225–60.
Miron PL. Mutational Analysis of NF-κB in Breast Cancer.
(Developmental Pilot Project) available at
http://www.dfhcc.harvard.edu/fileadmin/DFHCC_Admin/SPOR
Es/Breast/Penelope_Miron_Dev_Project.pdf
Sen R, Baltimore D. Multiple nuclear factors interact with the
immunoglobulin enhancer sequences. Cell 1986;46:705–16.
Ghosh S, Karin M. Missingpieces in the NF-nB puzzle. Cell
;109:S81–96.
Li Q, Verma IM. NF-κB regulation in the immune system. Nat
Rev Immunol 2002;2:725–34.
Tergaonkar V, Pando M, Vafa O, Wahl G, Verma I.p53
stabilization is decreased upon NFkappaB activation: a role for
NFkappaB in acquisition of resistance to chemotherapy. Cancer
Cell 2002;1(5):493–503.
Biswas DK, Martin KJ, McAlister C. Apoptosis caused by
chemotherapeutic inhibition of nuclear factor-nB activation.
Cancer Res 2003;63:290–5.
Wang Y, Paszek P , Horton CA, Kell DB, White MRH,
Broomhead DS, et al. Interactions among oscillatory pathways in
NF-kappa B signaling: BMC Systems Biology 2011;5:23–8.
Burkett M, Gilmore TD. Control of apoptosis by Rel/NF-nB
transcription factors. Oncogene 1991;8:6910–24.
Scott ML, Fujita T, Liou HC, Nolan GP, Baltimore D: The p65
subunit of NF-kappa B regulates I kappa B by two distinct
mechanisms. Genes & Development 1993;7(7a):1266–76.
Song HY, Rothe M, Goeddel DV. The tumor necrosis factorinducible zinc finger protein A20 interacts with TRAF1/TRAF2
and inhibits NF-kappaB activation. Proc Natl Acad Sci USA
;93(13):6721–5.
Wertz IE, O'Rourke KM, Zhou H, Eby M, Aravind L, Seshagiri
S, et al. De-ubiquitination and ubiquitin ligase domains of A20
downregulate NF-κB signalling. Nature 2004;430:694–9.
Ahmad M, Marui N, Alexander RW, Medford RM. Cell typespecific transactivation of the VCAM-1 promoter through an NF-
κB enhancer motif. J Biol Chem 1995;270:8976–83.
Paxton LL, Li LJ, Secor V, Duff JL, Naik SM, Shibagaki N.
Flanking sequences for the human intercellular adhesion
molecule-1 NF-κB response element are necessary for tumor
necrosis factor a-induced gene expression. J Biol Chem
;272:15928–35.
Aoudjit F, Brochu N, Belanger B, Stratowa C, Hiscott J, Audette
M. Regulation of intercellular adhesion molecule-1 gene by tumor
necrosis factor-a is mediated by the nuclear factor-kB
heterodimers p65/p65 and p65/c-Rel in the absence of p50. Cell
Growth Differ 1997;8:335–42.
Vandermeeren M, Janssens S, Borgers M, Geysen J.
Dimethylfumarate is an inhibitor of cytokine-induced E-selectin,
VCAM-1, and ICAM-1 expression in human endothelial cells.
Biochem Biophys Res Commun 1997;234:19–23.
Lee DH, Tam SS, Wang E, Taylor GR, Plante RK, Lau CY. The
NF-κB inhibitor, tepoxalin, suppresses surface expression of the
cell adhesion molecules CD62E, CD11b/CD18 and CD106.
Immunol Lett 1996;53:109–13.
Ray P, Yang L, Zhang DH, Ghosh SK, Ray A. Selective
upregulation of cytokine-induced RANTES gene expression in
lung epithelial cells by overexpression of IkBR. J Biol Chem
;272:20191–7.
Widmer U, Manogue KR, Cerami A, Sherry B. Genomic cloning
and promoter analysis of macrophage inflammatory protein
(MIP)-2, MIP-1 alpha, and MIP-1 beta, members of the
chemokine superfamily of proinflammatory cytokines. J Immunol
;150:4996–5012.
Blackwell TS, Christman JW. The role of nuclear factor-kappa B
in cytokine gene regulation. Am J Respir Cell Mol Biol
;17:3–9.
Gilmore TD. Clinically relevant finding. J Clin Investig
;100:2935–6.
Garside H, Stevens A, Farrow S, Normand C, Houle B, Berry A,
et al. Glucocorticoid ligands specify different interactions with
NF-kappa B by allosteric effects on the glucocorticoid receptor
DNA binding domain. J Biol Chem 2004;279(48):50050–9.
Ikeda A, Sun X, Li Y, Zhang Y, Eckner R, Doi T, et al.
p300/CBP-dependent and -independent transcriptional
interference between NF-kappa B RelA and p53. Biochem
Biophys Res Comm 2000;272(2):375–9.
Perkins ND. Integrating cell-signalling pathways with NF-κkB
and IKK function. Nat Rev Mol Cell Biol 2007;8:49–62.
Salminen A, Ojala J, Huuskonen J, Kauppinen A, Suuronen T,
Kaarniranta K. Interaction of aging-associated signaling cascades:
Inhibition of NF-kappa B signaling by longevity factors FoxOs
and SIRT1. Cell Mol Life Sci 2008;65(7-8):1049–58.
Wadgaonkar R, Phelps K, Haque Z, Williams A, Silverman E,
Collins T. CREB-binding protein is a nuclear integrator of nuclear
factor-kappa B and p53 signaling. J Biol Chem
;274(4):1879–82.
Culmsee C, Siewe J, Junker V, Retiounskaia M, Schwarz S,
Camandola S. Reciprocal inhibition of p53 and nuclear factor-κB
transcriptional activities determines cell survival or death in
neurons. J Neurosci 2003;23(24):8586–95.
Nakshatri H, Goulet RJ, Jr. NF-kB and breast cancer. Curr Probl
Cancer 2002;26:282–309.
Nakshatri H, Bhat-Nakshatri P, Martin DA, Goulet RJ, Jr., Sledge
GW, Jr. Constitutive activation of NF-nB duringprog ression of
breast cancer to hormone-independent growth. Mol Cell Biol
;17:3629–39.
Cao Y, Karin M: NF-kappaB in mammary gland development and
breast cancer. J Mammary Gland Biol Neoplasia 2003;8:215–23.
Cogswell PC, Guttridge DC, Funkhouser WK, Baldwin AS Jr.
Selective activation of NF-kappa B subunits in human breast
cancer: potential roles for NF-kappa B2/p52 and for Bcl-3.
Oncogene 2000;19:1123–31.
Huber MA, Azoitei N, Baumann B, Grunert S, Sommer A,
Pehamberger H, et al. NF-kappaB is essential for epithelialmesenchymal transition and metastasis in a model of breast
cancer progression. J Clin Invest 2004;114:569–81.
Edwards J, Tannahill C, Obondo C, Elsberger B, Mallon E,
Wilson C et al. Expression and activation of Akt and NFkB in
breast cancer patients. Euro J Cancer Suppl 2010;8(6):5–6.
J Ayub Med Coll Abbottabad 2010;22(3)
http://www.ayubmed.edu.pk/JAMC/PAST/22-3/Ayesha.pdf 221
Aggarwal BB. Nuclear factor-kappaB the enemy within. Cancer
Cell 2004;6:203–8.
Karin M, Cao Y, Greten FR, Li ZW: NF-kappaB in cancer:
from innocent bystander to major culprit. Nat Rev Cancer
;2:301–10.
Biswas DK, Shi Q, Bailey S. NF-kB activation in human breast
cancer specimens and its role in cell proliferation and apoptosis.
Proc Natl Acad Sci USA 2004;101:10137–42.
Biswas DK, Iglehart JD. Linkage between EGFR family receptors
and nuclear factor kappaB(NF-kappaB) signalling in breast
cancer. J Cell Physiol 2006;209(3):645‒52.
Singh S, Shi Q, Bailey ST, Palczewski MJ, Pardee AB, Iglehart
JD, Biswas DK. Nuclear factor-kappaB activation: a molecular
therapeutic target for estrogen receptor-negative and epidermal
growth factor receptor family receptor-positive human breast
cancer. Mol Cancer Ther 2007;6(7):1973–82.
Cristofanilli M, Buzdar AU, Hortobagyi GN. Update on the
management of inflammatory breast cancer. Oncologist
;8:141–8.
Smith I. Goals of treatment for patients with metastatic breast
cancer. Semin Oncol 2006;33:2S–5S.
Van Laere SJ, Van der Auwera I, Van den Eynden GG, Elst HJ,
Weyler J, Harris AL, van Dam P, et al. Nuclear factor-kappaB
signature of inflammatory breast cancer by cDNA microarray
validated by quantitative real-time reverse transcription-PCR,
immunohistochemistry, and nuclear factor-kappaB DNA-binding.
Clin Cancer Res 2006;12(11 Pt 1):3249–56.
Bertucci F, Finetti P, Rougemont J, Charafe-Jauffret E, Nasser V,
Loriod B, et al. Gene Expression Profilingfor Molecular
Characterization of Inflammatory Breast Cancer and Prediction of
Response to Chemotherapy. Cancer Res 2004;64:8558–65.
Van Laere S, Van der Auwera I, Van den Eynden GG, Fox SB,
Bianchi F, Harris AL, et al. Distinct molecular signature of
inflammatory breast cancer by cDNA microarray analysis. Breast
Cancer Res Treat 2005;93:237–46.
Lerebours F, Vacher S, Andrieu C, Espie M, Marty M, Lidereau
R. NF-kappa B genes have a major role in Inflammatory Breast
Cancer: BMC Cancer 2008;8:41.
Helbig G, Christopherson KW 2nd, Bhat-Nakshatri P, Kumar S,
Kishimoto H, Miller KD et al. NF-kappaB promotes breast cancer
cell migration and metastasis by inducing the expression of the
chemokine receptor CXCR4. J Biol Chem 2003;278(24):21631–8.
Published
Issue
Section
License
Journal of Ayub Medical College, Abbottabad is an OPEN ACCESS JOURNAL which means that all content is FREELY available without charge to all users whether registered with the journal or not. The work published by J Ayub Med Coll Abbottabad is licensed and distributed under the creative commons License CC BY ND Attribution-NoDerivs. Material printed in this journal is OPEN to access, and are FREE for use in academic and research work with proper citation. J Ayub Med Coll Abbottabad accepts only original material for publication with the understanding that except for abstracts, no part of the data has been published or will be submitted for publication elsewhere before appearing in J Ayub Med Coll Abbottabad. The Editorial Board of J Ayub Med Coll Abbottabad makes every effort to ensure the accuracy and authenticity of material printed in J Ayub Med Coll Abbottabad. However, conclusions and statements expressed are views of the authors and do not reflect the opinion/policy of J Ayub Med Coll Abbottabad or the Editorial Board.
USERS are allowed to read, download, copy, distribute, print, search, or link to the full texts of the articles, or use them for any other lawful purpose, without asking prior permission from the publisher or the author. This is in accordance with the BOAI definition of open access.
AUTHORS retain the rights of free downloading/unlimited e-print of full text and sharing/disseminating the article without any restriction, by any means including twitter, scholarly collaboration networks such as ResearchGate, Academia.eu, and social media sites such as Twitter, LinkedIn, Google Scholar and any other professional or academic networking site.
