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The transcriptional activity of NF-kB plays an important functional role in both inflammation and cancer, and these pathological roles are also intertwined in that many genes regulated by NF-kB contribute to both pathologies. In normal conditions, the induction of NF-kB’s pro-inflammatory gene expression

programming results in an effective response to insult or injury within the human body that can be resolved in a timely manner (Zhang and Sun 2015; Lawrence 2009). However, dysregulation of this immune response, often involving

constitutive activation of NF-kB, can lead to chronic inflammation and pathological immune-related disorders.

The relationship between NF-kB and cancer is multi-faceted. The most well-documented role of NF-kB signaling in cancer involves constitutive NF-kB activation and, specifically, the ability of NF-kB to regulate a myriad of genes that control cell proliferation, as well as apoptosis and cell survival. A long history of evidence suggests that the regulation of pro-proliferation genes and anti-

apoptotic genes goes hand-in-hand to promote tumorigenesis, and there is evidence to suggest that inhibiting the activity of NF-kB can reverse the

tumorigenic phenotype resulting from constitutive NF-kB activation and trigger apoptosis (Biswas et al. 2003; Karin and Lin 2002; Barkett and Gilmore 1999; Biswas et al. 2004).

The NF-kB gene expression profile responsible for tumor promotion is also believed to involve genes involved in the promotion of angiogenesis and metastasis. While the relationship between NF-kB and promotion of invasiveness

is not as well-studied as its dual role in prevention of apoptosis and promotion of proliferation, it has been shown that the NF-kB target gene interleukin-8 (IL-8) contributes to angiogenesis (Koch et al. 1992). Further, it has also been shown that inhibiting NF-kB resulted in a decrease in angiogenesis and tumor growth, as well as increased survival in mice, and was accompanied by reduced

expression of both IL-8 and another angiogenic gene, vascular endothelial growth factor (VEGF) (Huang et al. 2000).

Further, aside from the somewhat general roles NF-kB signaling plays in the progression of a variety of tumor types, NF-kB signaling plays a specific role in the development of leukemias and lymphomas (Karin et al. 2002). For

instance, for a specific subtype of diffuse large B-cell lymphoma (DLBCL),

constitutive activation of NF-kB is, in fact, required for cancer cell viability (Bidere et al. 2009). Also, certain germline mutations in NF-kB are particularly prevalent in certain leukemias and lymphomas resulting in a unique reliance of the cancer on NF-kB or a predisposition to the development of the cancer (Leeksma et al. 2017).

In breast cancer, NF-kB has been shown to upregulate genes implicated in cancer progression, including cyclin D1, cyclin-dependent kinase 2, and c-Myc (Wang et al. 2015). NF-kB activation in breast cancer has also been specifically linked to the upregulation of cytokines, as well as anti-apoptotic and pro-survival genes. Interestingly, a link has been determined between NF-kB activation and HER2-type breast cancer, wherein HER2 overexpression leads to an

(Merkhofer et al. 2010). Another study also determined that constitutive NF-kB activation led to the development of drug resistance in HER2-overexpressing breast cancer cells (Bailey et al. 2014).

It is also believed that NF-kB activation plays a particular role in breast cancer by interacting with tumor stroma and cancer stem cells to promote

epithelial-mesenchymal transition and metastasis. To this end, NF-kB signaling is known to lead to the upregulation of a variety of genes in breast cancers involved in the promotion of metastasis, and this process is believed to involve the ability of pro-inflammatory signaling from the tumor microenvironment to translate to NF-kB-mediated gene expression changes (Wang et al. 2015).

Aside from the role of NF-kB in promoting drug resistance in HER2-type breast cancer, it is also believed NF-kB activation may contribute to the

development of resistance to endocrine therapies such as tamoxifen, wherein crosstalk between constitutive NF-kB signaling activation and ER signaling acts to promote ER activity (Khongthong et al. 2019). Additionally, as might be expected, breast cancer cell treatment with chemotherapeutic agents including doxorubicin and taxanes such as paclitaxel has been shown to induce NF-kB activation to promote treatment resistance through the upregulation of pro- survival genes (Tergaonkar et al. 2003; Esparza-Lopez et al. 2013; Patel et al. 2000).

Interestingly, within cancer settings, NF-kB does not always participate in tumor promotion and prevention of cell death. In some cases, it has been shown that the activation of NF-kB can actually promote cell death. Specifically, it has

been shown that stimulation of NF-kB by interleukin 1 (IL-1) in co-stimulated epithelial carcinoma KB cells and keratinocytes resulted in increases in both tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis (Kothny-Wilkes et al. 1998), as well as UVB radiation-induced

apoptosis (Strozyk et al. 2006). Also, another study showed that disruption of NF- kB signaling by either inhibiting NF-kB with pyrrolidine dithiocarbamate (PDTC) or by transfection of mutant IkBa to prevent RelA/p65 nuclear translocation resulted in decreased sensitivity of neuroblastoma cells to doxorubicin treatment, again suggesting NF-kB can play a positive role in cell death mechanisms (Bian et al. 2001). Further, transfection of an antisense IkBa vector to reduce IkBa expression, thereby inducing increased NF-kB activation, resulted in increased sensitivity of breast cancer cells to paclitaxel-induced cell death (Huang and Johnson et al. 2000). While these examples of NF-kB acting to promote cell death and apoptosis may appear isolated, there is cell signaling evidence

supporting this role for NF-kB, in that DNA-damaging agents have been shown to lead to NF-kB-mediated upregulation of Fas ligand, a common activator of

extrinsic apoptotic pathways, thereby suggesting further that the role of NF-kB signaling in response to chemotherapeutic treatment may be complex

(Kasibhatla et al. 1998).