Breast cancer is a heterogeneous disease, yet it remains
possible to highlight common molecular signatures from
distinct tumour subtypes. A frequent feature found in
most breast cancer tumours is the constitutive activation
of NF-κB, a family of transcription factors that play
critical roles in cell survival, proliferation, infl ammation
and immunity . Deregulated NF-κB activation results
in the persistent nuclear localization of proteins such as
p50, p52, p65, cRel and RelB, which leads to the disrup-
tion of the balance between cell proliferation and death
through the upregulation of anti-apoptotic proteins .
The main NF-κB-activating pathways
Two major NF-κB-activating pathways have been charac-
terized, referred to as the classical or canonical and the
alternative or non-canonical pathways. Both rely on the
signal-induced phosphorylation and degradation of an
inhibitory molecule and the subsequent release and
nuclear shuttling of NF-κB proteins. Yet, both pathways
diff er by the signals that trigger them as well as by the
identity of the activated kinases, the inhibitory molecule
and the NF-κB proteins. Th e classical pathway is typically
triggered by pro-infl ammatory cytokines such as TNFα
or IL-1β and ultimately leads to the degradation of the
inhibitory molecule IκBα by the NF-κB essential modu-
lator (NEMO)/IκB kinase (IKK)γ-containing IKK com-
plex through a TAK1-dependent pathway  (Figure 1).
Th e p50/p65 heterodimer will then move into the nucleus
to induce the expression of genes involved in cell
prolifera tion and survival, infl ammation and innate
immunity. Th e alternative pathway triggers the partial
degradation of the inhibitory molecule p100 into p52
through a NF-κB-inducing kinase (NIK)-dependent path-
way (Figure 1). Th is cascade relies on an IKKα hetero-
dimer but not on NEMO/IKKγ and ultimately leads to
the nuclear shutt ling of p52/RelB dimers. Th is signalling
pathway plays a critical role in adaptive immunity .
The classical NF-κB-activating pathway in breast
Based on the key role of NF-κB in mammary epithelial
proliferation, architecture and branching during early
post-natal development [3,4], it was not surprising to see
that the constitutive NF-κB activation found in several
breast tumour cell lines has profound consequences in
the initiation and progression of breast cancer . NF-κB
is mostly activated in oestrogen receptor-negative (ER-
negative) and ErbB2-positive tumours [6,7]. Importantly,
a NEMO-binding domain (NBD) peptide, which acts as a
selective inhibitor of the IKK complex, blocked heregulin-
mediated NF-κB activation and induced apoptosis prefer-
entially in proliferating cells, showing that the classical
pathway largely contributes to tumour development .
Th ose initial reports were followed by studies that more
specifi cally addressed the role of NF-κB in breast tumour
development in vivo. A genetic approach in which the
classical NF-κB-activating path way is inhibited in defi ned
windows during polyoma middle T oncogene (PyVT)
tumourigenesis showed that interfering with this pathway
increases tumour latency and decreases tumour burden
. Th ese fi ndings are in agreement with data showing
the requirement of NF-κB for the induction and
Self-renewing breast cancer stem cells are key actors
in perpetuating tumour existence and in treatment
resistance and relapse. The molecular pathways
required for their maintenance are starting to be
elucidated. Among them is the transcription factor
NF-κB, which is known to play critical roles in cell
survival, infl ammation and immunity. Recent studies
indicate that mammary epithelial NF-κB regulates the
self-renewal of breast cancer stem cells in a model of
Her2-dependent tumourigenesis. We will describe here
the NF-κB-activating pathways that are involved in this
process and in which progenitor cells this transcription
factor is actually activated.
© 2010 BioMed Central Ltd
NF-κB, stem cells and breast cancer: the links get
Kateryna Shostak and Alain Chariot*
Interdisciplinary Cluster for Applied Genoproteomics (GIGA-Research), Unit
of Medical Chemistry and GIGA-Signal Transduction, University of Liege, CHU,
Sart-Tilman, 4000 Liège, Belgium
Shostak and Chariot Breast Cancer Research 2011, 13:214
© 2011 BioMed Central Ltd
RR, Ambrogio L, Hirozane-Kishikawa T, Hill DE, Vidal M, Meyerson M, Grenier
JK, Hinkle G, Root DE, Roberts TM, Lander ES, Polyak K, Hahn WC: Integrative
genomic approaches identify IKBKE as a breast cancer oncogene. Cell
20. Eddy SF, Guo SQ, Demicco EG, Romieu-Mourez R, Landesman-Borag E, Seldin
DC, Sonenshein GE: Inducible I kappa B kinase/I kappa B kinase epsilon
expression is induced by CK2 and promotes aberrant nuclear factor-kappa
B activation in breast cancer cells. Cancer Res 2005, 65:11375-11383.
21. Hutt i JE, Shen RR, Abbott DW, Zhou AY, Sprott KM, Asara JM, Hahn WC,
Cantley LC: Phosphorylation of the tumor suppressor CYLD by the breast
cancer oncogene IKK epsilon promotes cell transformation. Mol Cell 2009,
22. Gine stier C, Hur MH, Charafe-Jauff ret E, Monville F, Dutcher J, Brown M,
Jacquemier J, Viens P, Kleer CG, Liu S, Schott A, Hayes D, Birnbaum D, Wicha
MS, Dontu G: ALDH1 is a marker of normal and malignant human
mammary stem cells and a predictor of poor clinical outcome. Cell Stem
Cell 2007, 1:555-567.
23. Char afe-Jauff ret E, Ginestier C, Iovino F, Wicinski J, Cervera N, Finetti P, Hur MH,
Diebel ME, Monville F, Dutcher J, Brown M, Viens P, Xerri L, Bertucci F, Stassi G,
Dontu G, Birnbaum D, Wicha MS: Breast cancer cell lines contain functional
cancer stem cells with metastatic capacity and a distinct molecular
signature. Cancer Res 2009, 69:1302-1313.
24. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard
F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg
RA: The epithelial-mesenchymal transition generates cells with properties
of stem cells. Cell 2008, 133:704-715.
25. Liu SL, Dontu G, Wicha MS: Mammary stem cells, self-renewal pathways,
and carcinogenesis. Breast Cancer Res 2005, 7:86-95.
26. Kork aya H, Paulson A, Iovino F, Wicha MS: HER2 regulates the mammary
stem/progenitor cell population driving tumorigenesis and invasion.
Oncogene 2008, 27:6120-6130.
27. Merk hofer EC, Cogswell P, Baldwin AS: Her2 activates NF-kappa B and
induces invasion through the canonical pathway involving IKK alpha.
Oncogene 2010, 29:1238-1248.
28. Liu M, Sakamaki T, Casimiro MC, Willmarth NE, Quong AA, Ju X, Ojeifo J, Jiao X,
Yeow WS, Katiyar S, Shirley LA, Joyce D, Lisanti MP, Albanese C, Pestell RG:
The canonical NF-kappa B pathway governs mammary tumorigenesis in
transgenic mice and tumor stem cell expansion. Cancer Res 2010,
29. Cao YX, Luo JL, Karin M: I kappa B kinase a kinase activity is required for
self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells.
Proc Natl Acad Sci U S A 2007, 104:15852-15857.
30. Schr amek D, Leibbrandt A, Sigl V, Kenner L, Pospisilik JA, Lee HJ, Hanada R,
Joshi PA, Aliprantis A, Glimcher L, Pasparakis M, Khokha R, Ormandy CJ,
Widschwendter M, Schett G, Penninger JM: Osteoclast diff erentiation factor
RANKL controls development of progestin-driven mammary cancer.
Nature 2010, 468:98-102.
31. Gonz alez-Suarez E, Jacob AP, Jones J, Miller R, Roudier-Meyer MP, Erwert R,
Pinkas J, Branstetter D, Dougall WC: RANK ligand mediates progestin-
induced mammary epithelial proliferation and carcinogenesis. Nature
32. Prat t MAC, Tibbo E, Robertson SJ, Jansson D, Hurst K, Perez-Iratxeta C, Lau R,
Niu MY: The canonical NF-kappa B pathway is required for formation of
luminal mammary neoplasias and is activated in the mammary progenitor
population. Oncogene 2009, 28:2710-2722.
33. Visv ader JE: Keeping abreast of the mammary epithelial hierarchy and
breast tumorigenesis. Gene Dev 2009, 23:2563-2577.
34. Naug ler WE, Karin M: NF-kappa B and cancer - identifying targets and
mechanisms. Curr Opin Genet Dev 2008, 18:19-26.
35. Ilio poulos D, Hirsch HA, Struhl K: An epigenetic switch involving NF-kappa
B, Lin28, Let-7 microRNA, and IL6 links infl ammation to cell
transformation. Cell 2009, 139:693-706.
36. Jese lsohn R, Brown NE, Arendt L, Klebba I, Hu MG, Kuperwasser C, Hinds PW:
Cyclin D1 kinase activity is required for the self-renewal of mammary stem
and progenitor cells that are targets of MMTV-ErbB2 tumorigenesis.
Cancer Cell 2010, 17:65-76.
37. Char iot A: The NF-kappa B-independent functions of IKK subunits in
immunity and cancer. Trends Cell Biol 2009, 19:404-413.
38. Visv ader JE: Cells of origin in cancer. Nature 2011, 469:314-322.
39. Lim E, Vaillant F, Wu D, Forrest NC, Pal B, Hart AH, Asselin-Labat ML, Gyorki DE,
Ward T, Partanen A, Feleppa F, Huschtscha LI, Thorne HJ; kConFab, Fox SB, Yan
M, French JD, Brown MA, Smyth GK, Visvader JE, Lindeman GJ: Aberrant
luminal progenitors as the candidate target population for basal tumor
development in BRCA1 mutation carriers. Nat Med 2009, 15:907-913.
40. Moly neux G, Geyer FC, Magnay FA, McCarthy A, Kendrick H, Natrajan R,
Mackay A, Grigoriadis A, Tutt A, Ashworth A, Reis-Filho JS, Smalley MJ: BRCA1
basal-like breast cancers originate from luminal epithelial progenitors and
not from basal stem cells. Cell Stem Cell 2010, 7:403-417.
41. Naga ta Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP,
Nguyen NT, Hortobagyi GN, Hung MC, Yu D: PTEN activation contributes to
tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab
resistance in patients. Cancer Cell 2004, 6:117-127.
42. Iwai K, Tokunaga F: Linear polyubiquitination: a new regulator of NF-kappa
B activation. EMBO Rep 2009, 10:706-713.
Cite this article as: Shostak K, Chariot A: NF-κB, stem cells and breast cancer:
the links get stronger. Breast Cancer Research 2011, 13:214.
Shostak and Chariot Breast Cancer Research 2011, 13:214
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