Targeting the NFκB signaling pathways for breast cancer prevention and therapy

Abstract

The activation of nuclear factor-kappaB (NFκB), a proinflammatory transcription factor, is a commonly observed phenomenon in breast cancer. It facilitates the development of a hormone-independent, invasive, high-grade, and late-stage tumor phenotype. Moreover, the commonly used cancer chemotherapy and radiotherapy approaches activate NFκB, leading to the development of invasive breast cancers that show resistance to chemotherapy, radiotherapy, and endocrine therapy. Inhibition of NFκB results in an increase in the sensitivity of cancer cells to the apoptotic effects of chemotherapeutic agents and radiation and restoring hormone sensitivity, which is correlated with increased disease-free survival in patients with breast cancer. In this review article, we focus on the role of the NFκB signaling pathways in the development and progression of breast cancer and the validity of NFκB as a potential target for breast cancer prevention and therapy. We also discuss the recent findings that NFκB may have tumor suppressing activity in certain cancer types. Finally, this review also covers the state-of-the-art development of NFκB inhibitors for cancer therapy and prevention, the challenges in targeting validation, and pharmacology and toxicology evaluations of these agents from the bench to the bedside.

Fig. (1).. The main pathways of NFκB activation.

On the left is the TNFα-dependent canonical signaling pathway. The binding of TNFα to the TNF receptor, TNFR1, triggers the sequential recruitment of the adaptors, TRADD (TNFR1-associated death domain protein), RIP (Receptor-interacting protein) and TRAF2 (TNF receptor-associated factor 2), to the membrane. Then, TRAF2 mediates the recruitment of the IκB kinase (IKK) complex, composed of IKKα, IKKβ and NEMO (NF-kappa-B essential modulator), to the TNFR1 signaling complex, which causes IKKβ activation. The activation of IKKβ leads to IκBα phosphorylation on specific residues, which induces polyubiquitination through the binding of ubiquitin proteins, finally leading to its degradation through the proteasome pathway. The p50-p65 heterodimer then binds to specific κB sites and activates a variety of NFκB target genes coding for pro-inflammatory cytokines (such as IL-6) and chemokines. On the right is the alternative, non-canonical, pathway of NFκB activation. This pathway relies on the recruitment of the TRAF2-TRAF3 heterodimer to the CD40 receptor. TRAF3 links the E3 ligases c-IAP1/2 (cellular inhibitor of apoptosis 1/2) to the kinase, NIK (NFκB-inducing kinase). NIK is activated by phosphorylation, and is also subjected to a c-IAP1/2-dependent degradative polyubiquitination. IKKα homodimers are activated by NIK and phosphorylate the inhibitory molecule, p100, the partial processing (via proteasomal degradation) of which generates the NFκB protein, p52. p52 moves into the nucleus as a heterodimer with RelB to regulate the expression of genes involved in lymphoid organogenesis or coding for chemokines.

Fig. (2).. The components, functions, and regulation of NFκB.

This schematic diagram shows the upstream physiological and pathological stimuli and kinases involved in NFκB activation in the cytoplasm, and representative transcriptional activities in the nucleus.

Fig. (3).. The interaction between ER and NFκB in breast cancer.

(a) Mutual transrepression of the ER and NFκB in mammary epithelial tissue. NFκB can inhibit the estrogen receptor (ER) in different ways. The activation of Akt inhibits the activity of FOXO3A, which plays an important role in the synthesis of the ER. Consequently, blocking FOXO3A activity leads to a reduction in the transcription of the ER. Another mechanism by which NFκB can inhibit the ER is by stimulating the activity of the enhancer of zeste homolog 2 (EZH2), which then inhibits the ER. Finally, NFκB (RelB) can also inhibit ER transcription by upregulating Blimp1. (b) The ER represses NFκB by blocking its nuclear translocation by increasing the transcription of the cytoplasmic NFκB subunit. ER signaling can activate the PI3K signaling pathway, leading to cytoplasmic accumulation of NFκB while inhibiting its nuclear translocation. Another mechanism by which the ER inhibits NFκB activity is by preventing it from binding to DNA.