Journal of the Senologic International Society

The World Society fo Breast Diseases

Volume 2. Issue 1. 2013

REVIEW ARTICLE

Molecular Mechanisms of NF-κB

on Cancer Promotion and
Progression

Pires, B. R. B.¹; Mencalha, A. L.¹,²; Abdelhay, E.¹

¹ Instituto Nacional de Câncer José Alencar Gomes da Silva, Divisão

de Laboratórios do CEMO, Laboratório de Célula-Tronco, Rio de
Janeiro - RJ, Brazil

² Universidade do Estado do Rio de Janeiro, Instituto de Biologia

Roberto Alcântara Gomes, Departamento de Biofísica e Biometria,
Rio de Janeiro - RJ, Brazil

Abstract
Nuclear Factor - kappa B (NF-κB) is a transcription factor family that
regulates a large number of genes involved in important
physiological processes, including cell growth, survival,
inflammation and immune responses. More recently, NF-κB
signaling has been associated to cancer development by providing a
link between inflammation, tumour microenvironment and
metastasis. Moreover, NF-κB is implicated in chemotherapy and
radiotherapy resistance by protecting cancer cells against apoptosis.
Recent reports have showed that NF-κB signaling pathway should
receive attention for development of anti-proliferative and anti-
metastatic cancer treatments. This review discusses regulatory
mechanisms and biological significance of NF-κB activation to
cancer development processes.

Keywords: NF-{kappa}B; NF-kB; cancer promotion; cancer

progression

 
 SIS Journal - Journal of the Senologic International Society. Volume 2. Issue 1. 2013

Introduction
Cancer is a multifactor disease responsible for more than 7 million
deaths each year. Commonly, there are necessary some stages for its
development: initialization, promotion and progression. The first
consists in a step that triggers cellular abnormality, known as
initialization. The second has as goal growth and establish an
efficient microenvoirment, and it is known as promotion. The third
can be defined as a migratory step, because promotes cancer cells
dissemination. This last is called as progression. A lot of genes can
participate of almost all these stages though their signaling
networks, and NF-κB is one of them.

The NF-κB complex has been described as a key transcription factor

of a large number of biological processes, including cell
proliferation, differentiation, immune responses and inflammation.
NF-κB complex is located in cytoplasm while bounds to inhibitor IκB
proteins. To the NF-κB complex be released from its inhibitor ligand,
the IκB protein must be phosphorylated by the IκB kinase (IKK),
which leads IκB to ubiquitination and subsequent degradation by
26s proteasome. NF-κB complex is then translocated into the
nucleus where it can act as a transcription factor. This complex has
more than 150 regulation gene targets and the more abundant
heterodimer found is p65/p50 [1]. Activation of NF-κB signaling can
be initiated by a large number of extracellular stimuli involved in
inflammatory responses, such as cytokine signaling (TNF-α (Tumor
necrosis factor-alpha) and IL-1β (Interleukin-1 beta)), prokaryotic
infection (through the LPS (Lipopolysaccharide) signaling mediated
by TLR-4 (Toll Like Receptor-4)) and ROS (Reactive oxygen species)
[2].

Link between NF-κB and Hallmarks of Cancer

Several anti-apoptotic genes, such as Bcl-2 and Bcl-xL, are molecular
targets of the transcription factor NF-κB. Besides, NF-κB also acts
inducing expression of mitogenic proteins like c-Myc and Cyclin D1,
which control the tumor mass growth. Moreover, persistent NF-κB
activation has also been related to chemo and radiotherapy
resistance, through apoptosis inhibition and growth stimuli [3]. In
breast cancer, for example, the more aggressive phenotype has
been associated with the p65 (NF-κB subunit) overexpression which
allows tumor growth independently of external signalization, such
as steroid hormones [4].
 SIS Journal - Journal of the Senologic International Society. Volume 2. Issue 1. 2013

In the last 5 years, the association between inflammation and

cancer development has been largely discussed. An elegant review
[5] about this theme included inflammation as the seventh hallmark
of cancer and emerged the concept of inflammation as a promoter
of genome mutations and instability. Chronic inflammation
environment has been associated with high level of RNS (Reactive
nitrogen species) and ROS, potent DNA-damaging agents, which
was directly linked to chromosomal abnormalities, genetic
mutations and cancer promotion [6].

Several data indicated a positive feedback between NF-κB activation

and inflammatory signaling that it favors tumor development. In
this scenario, inflammatory interleukins activate NF-κB and
consequently up-regulate TNF-α expression. Secretion of TNF-α
recruits immune system cells that potentiates inflammation process,
creating a positive feeding system. Beyond interleukins, NF-κB could
also be indirectly activated by microorganisms. For example, LPS
secreted by gram-negative bacteria stimulates NF-κB activation. One
classic example is Helicobacter pylori infection associated to
stomach carcinomas development [5]. Furthermore, viral infections
also contribute to NF-κB levels elevation. Viral ssRNA (single strand
RNA) and dsRNA (double strand RNA) stimulate TLRs pathways that
culminate on NF-κB canonical pathway activation. One of these
viruses which activate this receptor and usually can be associated to
cancer development is HTLV-1 (Human T-lymphotropic virus Type 1).
Both examples demonstrate the link between NF-κB activation by
microorganisms, persistent infections and cancer promotion [3]. The
interleukins and chemokine secreted induce inflammatory cells
migration (such as tumor-associated macrophages) until neoplastic
cells which also interact with stromal cells establishing a tumour
microenvironment that supports the malignancy. In this
microenvironment, a lot of growth factors (FGF (Fibroblast Growth
Factor), EGF (Epidermal Growth Factor), VEGF (Vascular endothelial
growth factor)) and metastasis related proteins such as MMPs
(Matrix metalloproteinase) and TGF-β (Transforming growth factor
beta) are produced, creating a complex system with diverse features
like proliferative signaling, survival, angiogenesis, invasion and
metastasis.

DNA Repair, Drug Resistance and NF-κB

 SIS Journal - Journal of the Senologic International Society. Volume 2. Issue 1. 2013

One new view about cancer development is Mutator Phenotype

Theory, which unlike classic model of carcinogenesis, proposes that
cancer is not initialized by external factors alone. Thus, cancer cells
are consequences of a lot of intra or extracellular components that
modify relevant processes such as replication and DNA repair which
are crucial to maintenance of physiological integrity of cell. When
these processes are corrupted, unrepaired DNA cells continue to
divide generating new cells with thousands of mutations [7]. The
NF-κB has a crucial role on these events by controlling some
proteins that effectively avoid cellular transformation, such as p53,
the genome guardian. In fact, several authors have proposed that
the most important influence of NF-κB on genomic instability could
be through p53 protein [8].

Radiotherapy treatment generates DNA double strand breaks (DNA-

DSB) and activates ATM homodimer that upregulates p53. If DNA
damages are considered irreparable by p53, cell is triggered to
apoptosis or to cell cycle arrest. Increased NF-κB levels inside
maligned cells, represses TP53 what ensure cancer cells survival and
replication, even in presence of DNA damages.

Chemotherapy treatment is focused on more specific targets than

radiotherapy. Usually, it has as direct action on mechanism of signal
transducers and membrane receptors, such as Trastuzumab that
blocks HER2/neu (Human Epidermal growth factor Receptor 2 ) [9]
or Tamoxifen [10] that acts as an antagonist of estrogen receptor in
breast cancer cells. Generally, the first-line chemotherapics are
based on a wide spectrum cellular targets acting against replication
or mitosis occurrence. For example, Doxorubicin that intercalates to
DNA and inhibits topoisomerase II action [11], and Cisplatin [12]
that promotes covalent DNA interstrand crosslinks. Another
chemotherapeutic commonly used is Paclitaxel responsible for
disturbing metaphase spindle formation during mitosis [13]. These
drugs induce DNA/cell replication stalling and collapse,
preferentially, in the fast replication cells such as cancer cells. All
these three drugs have irreversible mechanisms of action
generating DNA damages that are recognized by a class of proteins
known as “genome inspectors” that detect damage and trigger the
repair system. If DNA repair fails in the DNA integrity maintenance,
this same signaling will lead to cell death by triggering, mainly,
apoptosis machinery. In order to survive, cancer cells have to make
these damages unnoticed by overexpressing anti-apoptotic genes
and by reducing pro-apoptotic ones [6]. According to these cellular
 SIS Journal - Journal of the Senologic International Society. Volume 2. Issue 1. 2013

events, the NF-κB signaling is the main pathway responsible for

survival of cancer cells.

NF-κB and Metastasis

During embryonic development, transcription factors related to
epithelial to mesenchymal transition (EMT) are responsible for
control of cell morphology and architecture of neural crest and
mesoderm formation. These transcription factors are supposed to
be also regulated by another transcription factor: NF-κB complex
[14]. After embryogenesis, most of genes involved in this
mechanism are inactivated, but this entire regulation pattern is
recovered in cancer development. These evidences arose from
cancer stem cell concept that shows cancer expression patterns
similarity to embryonic development [6]. One of the malignity gain
theory is the EMT pattern activation, where transcription factors
such as SNAIL, SLUG, ZEB1, SIP1 and TWIST1 repress adhesion
molecules (E-cadherin, Claudins and Occludins) and stimulate
markers of mesenchymal phenotype (N-cadherin, Vimentin and
Fibronectin).

Many studies reported a link between increased NF-κB activity and

poor prognostic, where overexpression of NF-κB has been directly
associated to increase of metastasis [15, 16, 17]. However, it is
important to understand which mechanisms are linked to metastasis
and subsequent death. Besides contribution of EMT to metastasis,
NF-κB also induces expression of uPA (urokinase-type plasminogen
activator) and MMPs, which has been described as effectors of
extracellular matrix degradation, what allows mass cancer
extravasations and metastasis [18].

Conclusion
NF-κB has shown a relevant significance to activate and support
cancer development and maintenance. In cancer context, its role
overtakes chemokine regulation, because it dictates inflammatory
aggravation, tumour microenvironment formation and radio/chemo
treatment effectiveness. Several reports have supported that
activation of NF-κB signaling is the major marker of a high-risk of
carcinomas development, such as breast, renal, ovarian, pancreatic,
prostate, head and neck cancers. Additionally, NF-κB is pointed to
be a metastasis potential predictor, which indicates this
 SIS Journal - Journal of the Senologic International Society. Volume 2. Issue 1. 2013

transcription factor as a potential molecular target to metastasis

inhibition.

Acknowledgements
The authors thank Rafael Costa e Silva, Dr. Gerson Ferreira and Dr.
Carolina Panis for their great comments and suggestions during the
writing process of this paper. We acknowledge financial support
from CNPq (National Counsel of Technological and Scientific
Development) and FAPERJ (Carlos Chagas Filho Foundation for
Research Support of the State of Rio de Janeiro).

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