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P Khongthong et al. Nuclear factor kappa B and breast cancer

R369–R380

-19-0087

REVIEW

The NF-KB pathway and endocrine therapy resistance in breast cancer

Phungern Khongthong, Antonia K Roseweir and Joanne Edwards

Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of MVLS, University of Glasgow, Glasgow, UK

Correspondence should be addressed to J Edwards: joanne.edwards@glasgow.ac.uk

Abstract

Breast cancer is a heterogeneous disease, which over time acquires various adaptive changes leading to more aggressive biological characteristics and development of treatment resistance. Several mechanisms of resistance have been established; however, due to the complexity of oestrogen receptor (ER) signalling and its crosstalk with other signalling networks, various areas still need to be investigated. This article focusses on the role of nuclear factor kappa B (NF-KB) as a key link between inflammation and cancer and addresses its emerging role as a key player in endocrine therapy resistance. Understanding the precise mechanism of NF-KB-driven endocrine therapy resistance provides a possible opportunity for therapeutic intervention.

Introduction

Oestrogen receptor α-positive (ER+) breast cancer constitutes more than 70% of all breast cancers (Cardoso et al. 2012). Both early and metastatic disease are treated effectively with endocrine therapies, which downregulate oestrogen receptor (ER) signalling, leading to tumour growth inhibition (Cardoso et al. 2012). The three main groups of endocrine therapy are selective oestrogen receptor modulators, including tamoxifen and raloxifene, which acts as an oestrogen antagonist to bind to ER and further recruit transcriptional co-repressor instead of co-activators, leading to inhibition of tumour growth (Legha 1988); selective oestrogen receptor downregulators (SERDs), including fulvestrant, which prevents ER dimerization and induce its degradation (Wardell et  al. 2011); and aromatase inhibitors (AIs), including anastrozole, letrozole and exemestane, which inhibit the enzyme aromatase resulting in reduction of oestrogen levels through the blockade of testosterone conversion to oestrogens both in the tumour and peripheral tissue (Baum et al. 2003). However, a significant number of the patient fail to

respond to endocrine therapies as a result of either de novo or acquired resistance (Liu et al. 2017).

Many comprehensive reviews (Riggins et  al. 2007, Clarke et  al. 2009, Zhao & Ramaswamy 2014, Liu et  al. 2017, AlFakeeh & Brezden-Masley 2018, Masuda et  al. 2018) summarize the mechanisms of endocrine therapy resistance, including (i) the loss of ER expression or mutation of the ER that causes constitutive activation regardless of oestrogen; (ii) the amplification and upregulation of ER co-activators such as amplified in breast 1 (AIB1, also known as steroid receptor co-activator-3 (SRC3)), that can increase the activity of ERs; (iii) the upregulation of alternative oncogenic pathways such as phosphatidylinositol 3-kinase/a serine-threonine-specific protein kinase/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway resulting in increased activity of protein kinase pathways; (iv) the amplification and overexpression of gene regions that encode oncogenic proteins and transcription factors to promote cancer cell survival, invasion and metastasis; and (v) the deregulation of the proteins that control cell

Endocrine-Related Cancer (2019) 26, R369–R380

6

Key Words

f NF-KB

f endocrine therapy resistance

f breast cancer

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cycle machinery such as the cyclin-dependent kinases (CDKs), resulting in dysregulated cellular proliferation. Among these mechanisms, mTOR deregulation is considered clinically relevant and the mTOR inhibitor everolimus plus exemestane is included as an option for ER-positive advanced disease; however, this combination failed to improve overall survival in clinical trials (Baselga et al. 2012). In addition, due to double improvement in progression-free survival, palbociclib, a highly selective inhibitor of CDK4/6 kinases, in combination with letrozole had recently approved as first-line endocrine therapy for postmenopausal ER-positive, HER2-negative advance breast cancer (Finn et al. 2015). Despite the recent advances in therapeutic approach, metastatic breast cancer is incurable, and finally will develop treatment resistance, further increasing the complexity of molecular interactions. Therefore, identifying the novel driving factors that modulate oestrogen signalling and other important pathways still need to be addressed.

Nuclear factor kappa B (NF-KB) is a key transcription factor that links inflammation with cancer and is demonstrated as being involved in the tumorigenesis of breast cancer and endocrine therapy resistance. However, the molecular mechanisms of how NF-KB contributes to endocrine therapy resistance are still unclear. This article will summarize the currently available evidence that supports the promising role of NF-KB pathway in the mechanism of endocrine therapy resistance, in order to elucidate NF-KB as a potential novel target for overcoming this resistance.

NF-KB signalling

The NF-KB family of inducible transcription factors are composed of five members, including p50, p52, p65 (RelA), RelB and c-Rel, all of which share an N-terminal Rel homology domain (RHD) (Zhang et  al. 2017). RHD contains a nuclear localization sequence, and is responsible for sequence-specific DNA binding, dimerization and interaction with ankyrin repeat motifs, which are present in IκB inhibitory proteins (Zhang et  al. 2017). The ‘inhibitor of κB’ (IκB) proteins include IκBα, IκBβ, IκBγ, IκBϵ, BcL-3, the precursors p105 and p100, and the Drosophila protein Cactus (Zhang et  al. 2017). Among them, IκBα, IκBβ and IκBϵ are the most important regulators of NF-KB. NF-KB dimers bind to κB sites within the promoters or enhancers of target genes, which bare 5’-GGGRNWYYCC-3’ (N, any base; R, purine; W, adenine or thymine; Y, pyrimidine), and regulate transcription of

their target genes through the recruitment of co-activators and co-repressors (Zhang et  al. 2017). The potent transcription activation domain (TAD) is found only in p65, c-Rel and RelB. Due to the lack of TADs, dimers of p50 or p52 may mediate only transcriptional repression (Zhang et al. 2017).

In unstimulated cells, homo- or heterodimers of NF-KB are bound to their inhibitors and the IκB proteins are sequestered in the cytoplasm (Zhang et  al. 2017). Upon activation, NF-KB translocates to the nucleus to interact with κB site to induce transcription of the target genes (Zhang et  al. 2017). The most frequently recognized NF-KB pathways are the canonical and non-canonical pathway (Zhang et  al. 2017). The canonical NF-KB pathway is activated by pro-inflammatory cytokines such as TNF-α and interleukin-1 (IL-1), T- and B-cell mitogens, bacterial liposaccharide (LPS), viral proteins, and physical and chemical stress (Karin & Ben-Neriah 2000, Hoesel & Schmid 2013) (Fig. 1). A first step in the canonical pathway is the activation of transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1), which further activates a trimeric IkB kinase (IKK) complex that is composed of regulatory (NF-KB essential modulator (NEMO or IKKγ)) and catalytic (IKKα and IKKβ) subunits (Zhang et al. 2017). The IKK complex then phosphorylates IκB at specific serine residues, which results in polyubiquitination and subsequent proteasomal degradation of IκB, followed by nuclear translocation of NF-KB, mainly the p50/p65 heterodimer (Zhang et  al. 2017). The heterodimer then binds to the κB site and activates numerous genes that involve in inflammatory and immune responses, including cytokines, chemokines, inflammatory mediators, adhesion molecules and apoptosis inhibitors (Hoesel & Schmid 2013, Lim et  al. 2016, Zhang et  al. 2017). In contrast to the canonical pathway that responds rapidly to signals from the diverse receptors, the non-canonical pathway specifically responds to a small group of receptors, including lymphotoxin-β receptor (LTβR), B-cell activating factor belonging to TNF family receptor (BAFFR), CD40 and receptor activator for NF-KB (RANK), as summarized in recent comprehensive review (Sun 2012, 2017). Upon binding to its specific ligand, these receptors activate the kinase NF-KB-inducing kinase (NIK), which, in turn, phosphorylates and activates IKKα. Activated IKKα then phosphorylates p100/RelB heterodimer at the carboxyterminal serine residues of p100, subsequent to proteasomal degradation of the C- terminal IκB-like structure of p100, resulting in processing of p100 to p52 and nuclear translocation of p52/RelB

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(Sun 2012, 2017) (Fig. 2). Activated p52/RelB heterodimer then binds to the specific κB enhancer and subsequently activates transcription of its target genes that are involved in many biological function, including secondary lymphoid organogenesis, B-cell maturation and survival, dendritic cell maturation and differentiation of osteoclasts (Sun 2017). Together, it is not surprising that NF-KB serves as a key player in the immune system, cell survival, differentiation, proliferation and apoptosis. Moreover, a number of studies have confirmed NF-KB is key for crosstalk between inflammation and cancer (Hoesel & Schmid 2013, Zhang et al. 2017).

NF-KB signalling in breast cancer

A genetic analysis using a mouse model demonstrated that NF-KB plays a critical role in regulating proliferation of the mammary epithelial cells during pregnancy, which is controlled by a linear cascade of at least six components of the NF-KB pathway, including RANKL, RANK, IKKα, IkBα, p50/p65 and CyclinD1 (Cao et  al. 2001). In addition, a growing body of literature demonstrated that deregulation or constitutive activation of the NF-KB pathway is involved in tumorigenesis of breast cancer and is associated with the hormone-independent setting

(Nakshatri et  al. 1997, Sovak et  al. 1997, Nakshatri & Goulet 2002, Zhou et al. 2005b).

With regard to endocrine therapy resistance, studies have demonstrated that (i) increasing p65 expression was seen in MCF7/LCC9 cell (ER-positive, oestrogen independent for growth and anti-oestrogen cross-resistant) and MCF7/RR cells (ER-positive, oestrogen-independent for growth, tamoxifen resistant and fulvestrant sensitive), compared with MCF-7 control cells (Nehra et  al. 2010); (ii) increasing basal transcriptional activity of NF-KB was shown in MCF7/RR cells compared with MCF-7 control cells (Nehra et  al. 2010); (iii) using the NF-KB-inhibitor parthenolide resulted in decreased cell proliferation, and significant inhibition of NF-KB-dependent transcription in both resistance cell lines, compared to MCF-7 cells (Nehra et al. 2010); (iv) enhanced NF-KB and AP-1 transcriptional activity was found in tamoxifen-resistant breast cancer cell and NF-KB and AP-1 regulated gene expression was suppressed after treatment with the NF-KB inhibitor, parthenolide, or the proteasome inhibitor, bortezomib (Zhou et al. 2007); and (v) high DNA-binding activity of the p50 subunit of NF-KB is a potential prognostic marker to identify a high-risk subset of ER-positive primary breast cancer, which are found to have early relapse disease despite adjuvant treatment with tamoxifen (Zhou et  al. 2005a). Collectively, these finding support a crucial role

Figure 1The NF-KB pathway. The canonical pathway is induced by TNFα, IL1 and various other stimuli, and is an IKKβ-dependent cascade. Activation of this cascade leads to the phosphorylation of IkBα resulting in degradation by the proteasome. This releases the NF-KB complex and allows it to translocate to the nucleus. The non-canonical pathway is induced by specific stimuli such as lymphotoxin α and is an IKKα-dependent cascade. Activation of this cascade results in phosphorylation of NIK, followed by phosphorylation of IKKα and subsequent phosphorylation of the p100 NF-KB subunit. This subunit is then processed to p52, which leads to the activation of the p52-RelB heterodimer. The heterodimer can then translocate to the nucleus where it controls the transcriptional processing of its target genes. A full colour version of this figure is available at https://doi.org/10.1530/ERC-19-0087.

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for the NF-KB pathway in endocrine therapy resistance of breast cancer.

Crosstalk between NF-KB and ER signalling in endocrine therapy resistance breast cancer

Many comprehensive reviews have demonstrated that multiple mechanisms are involved in the crosstalk between NF-KB and ER. NF-KB directly interacts with the DNA-binding function of ER through several mechanisms, such as collaboration with FOXA1 to enhance latent ER-binding sites, and induce translation of their synergistic genes (Franco et al. 2015). In addition, NF-KB influences ER through association with its ER co-activator

or co-repressor, which will then alter ER transcriptional activity (Park et al. 2005). Similar to ER, NF-KB has been reported to have a role as a downstream effector for the growth factor pathway, which is recognized to be involved in both ligand-dependent and non-ligand-dependent ER activation, leading to resistance to a wide range of anti-oestrogen drugs (Zhou et al. 2005a, Sas et al. 2012, Frasor et al. 2015). Moreover, NF-KB plays a key role in the anti-apoptotic pathway and immune surveillance mechanisms, which are demonstrated to be part of endocrine resistance (Hu et  al. 2015, Lim et  al. 2016). In addition, NF-KB repression of ER activity has also been demonstrated. The NFκB subunit, RelB, induces the expression of the zinc finger repressor B-lymphocyte-induced maturation protein (BLIMP1), which can bind to the ER promoter

IKKγ

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Figure 2Crosstalk between NF-KB, ER signalling and other oncogenic pathway in endocrine resistance breast cancer. (A) PKCθ activates AKT, which in turn induces nuclear exportation of FOXO3a, resulting in decreased ERα transcriptional activity, leading to re-activation of c-Rel activity, followed by proliferation and an invasive phenotype transformation of breast cancer. (B) Upon activation with PI3K, IKKα phosphorylates both ER and SRC3 to further increase their transcriptional activity and acetylates E2F1 to increase the expression of E2F1-regulated genes, followed by increased cell cycle progression. (C) Upon co-stimulation with E2+TNFα, NF-KB and the Forkhead protein FoxA1 combine and locate new ER-binding sites named as a latent enhancer that controls up- or downregulation of a new set of synergistically regulated gene. (D) The NF-KB pathway as described in Fig. 1. (E) Upon TNF-α stimulation, NF κB p65 subunit bind to CSN5 promoter and promotes its transcription which subsequently induces its binding to PD-L1 and further deubiquitinates and stabilizes this protein, resulting in prevention of immune surveillance. (F) NF-KB is involved in the apoptotic machinery through transcriptional deregulation of pro-apoptotic (BAX, BAK, BAD and BCLXS) or anti-apoptotic proteins (BCL2, BCLXL and BCLW). NF-KB inhibits apoptosis in resistant cell through increased BCL2 expression, which further alters the BCL2:BAX ratio and inhibits apoptosis and modulates caspase 8 to further affect BCL2 resulting in inhibited apoptosis. (G) Accumulation of unfolded or misfolded proteins is detected by endoplasmic reticular transmembrane receptors such as inositol-requiring protein-1 (IRE1), which then activates XBP1 to enhance the unfolded protein response, which then promote phagocytosis. A full colour version of this figure is available at https://doi.org/10.1530/ERC-19-0087.

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region and repress ER transcription (Wang et  al. 2009). Currently, increasing evidence demonstrates that NF-KB is a crucial part in the complexity of the endocrine resistance setting within breast cancer.

NF-KB and ERS1 mutation in endocrine therapy resistance breast cancer

Oestrogens (mainly 17β-estradiol) are a group of steroid hormones that control cell growth and differentiation. Oestrogen binds to ER that exists in two isoforms, ERα and ERβ, which are encoded by two particular genes, ESR1 and ESR2, respectively. While ERα plays a key role in regulating genes transcription that is involved in the mitogenic pathway in breast cancer, the role of ERβ as a transcription factor remains unclear.

ER regulates transcription of its target gene through classical genomic, non-classical genomic and non-genomic pathways (Shou et al. 2004, Sas et al. 2012, Zhao & Ramaswamy 2014). The classical genomic pathway initiates with the binding of oestrogen to ER resulting in the release of heat shock protein (hsp) 90, followed by ER dimerization and nuclear translocation, where it can directly bind to the oestrogen response elements (EREs) in target genes (Shou et  al. 2004, Sas et  al. 2012, Zhao & Ramaswamy 2014). In contrast, in the non-classical genomic pathway, ER dimers do not bind to the EREs directly, but associate with other transcription factors prior to binding (Shou et al. 2004, Sas et al. 2012, Zhao & Ramaswamy 2014). Whereas, in the non-genomic pathway, upon binding to oestrogen, ER activates other pathways, including the mitogen-activated kinase pathway (MAPK) and the PI3K-AKT-mTOR pathway, to promote cell survival, proliferation and angiogenesis (Shou et  al. 2004, Sas et  al. 2012, Zhao & Ramaswamy 2014). Furthermore, activation of ER by growth factor signalling factors such as IGF and epidermal growth factor receptors (EGFRs) can mediate ER activation by inducing its phosphorylation, which can then translocate to the nucleus to bind to EREs, independent of oestrogen binding. Several mechanisms of endocrine therapy resistance have been identified, many of which are related to the complex function of ER and its crosstalk with the other cellular pathway as described above. Therefore altered ER function, which results from ESR1 mutation or ER loss of function, has been established as one of the major resistance mechanisms (Barone et al. 2010).

ESR1 mutations rise from 2% in the primary tumour to nearly 30 % in metastatic disease and the endocrine-resistant setting (Barone et  al. 2010, Jeselsohn et  al.

2014). These mutations enhance stabilization of the active conformation of ER, leading to constitutive activation and AI resistance (Barone et  al. 2010, Tryfonidis et  al. 2016). It has been demonstrated that there is a synergistic effect between NF-KB and ER that enhances expression of oncogenic proteins as described in the following section, it is not surprising therefore that ESR1 mutations might indirectly crosstalk to NF-KB pathway through the promotion of ER activity. Due to limited current evidence that reports a role for NF-KB in ER-positive breast cancer, patients carrying ESR1 mutations still need further study.

NF-KB and FOXA1 is required for TNFα to modulate latent ER-binding sites to reshape the breast cancer cell transcriptome

Increasing evidence reveals that inflammation plays a key role in maintaining the tumour microenvironment and promotes a more aggressive phenotype of ER-positive tumour (Baumgarten & Frasor 2012). In contrast to the potent mitogenic effect of oestrogens in breast cancer cells, pro-inflammatory signalling in the tumour microenvironment can either promote or inhibit tumour proliferation, depending on the particular context (Ben-Neriah & Karin 2011). NF-KB is a crucial transcription factors for pro-inflammatory signalling and is required for TNFα to promote crosstalk between mitogenic and pro-inflammatory signalling pathways in breast cancer cells (Franco et al. 2015).

By using chromatin immunoprecipitation (ChIP) for ER and the p65 subunit of NF-KB, three distinct sets of ERα-binding sites or enhancers were identified upon co-treatment with E2+TNFα, with a high prevalence of p65 and ESR1 motifs found to be gained at ERα-binding site, indicating functional interactions between ER and NF-KB across the genome (Franco et  al. 2015). In addition, upon co-stimulation with E2+TNFα, NF-KB and the Forkhead protein, FoxA1 (a well-established pioneer factor for ER), combine and locate new ER-binding sites that are found in less-accessible regions on the genome and are not recognized by the classical oestrogen-induced ER cistrome (Franco et al. 2015). Addition of TNFα to E2 alters extensive gene expression programme results in the up- or downregulation of a new set of genes, which were unchanged by either E2 or TNAα alone. The new sets of gene that arise from this transcriptome are involved in variety of cellular processes, including cellular signalling, protein and lipid metabolism, proliferation, programmed cell death and apoptosis (Franco et al. 2015).

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Moreover, the Gene Expression-Based Outcome for Breast Cancer Online tool was used to examine the association between the unique E2 + TNFα-regulated transcriptome and clinical outcome (Franco et al. 2015). The result demonstrated that this group of gene sets are influential predictors of clinical outcomes; however, good or poor outcomes depend on the particular breast cancer types (Franco et  al. 2015). For example, high expression levels of E2+TNFα de novo and synergistically upregulated gene sets are associated with high overall survival in patient with ER-positive, lymph node-positive tumours and are associated with low overall survival in patients with untreated tumour (Franco et  al. 2015). Furthermore, high expression levels of E2+TNFα de novo and synergistically downregulated gene sets are associated with low overall survival in patient with ER-positive and lymph node-negative tumours (Franco et al. 2015).

Collectively, these results indicate that NF-KB is a key link between pro-inflammatory and mitogenic signalling, leading to creation of latent ER-binding site that reshape patterns of gene expression, and further contribute to varied cellular responses and clinical outcomes in particular breast cancer subtypes.

NF-KB and the PKCθ/AKT/FOXO3a axis induce invasive transformation of breast cancer through repressing of ER transcription

The serine/threonine protein kinase C θ (PKCθ) has been reported to regulate c-Rel-driven mammary tumour in mouse models (Guo & Sonenshein 2004). In the normal mammary gland, FOXO3a binds to the Forkhead box elements in the ER promoter and maintains a normal epithelial cell phenotype via induced transcription of its target genes p27Kip1 (a member of the universal CDK inhibitor) and ERα, which in turn represses c-Rel activity (Guo & Sonenshein 2004). In the invasive phenotype transformation of breast cancer, PKCθ activates AKT, which in turn induces nuclear exportation of FOXO3a, resulting in decreased ERα transcription activity, leading to re-activation of c-Rel activity, followed by proliferation and invasive phenotype transformation of breast cancer (Guo & Sonenshein 2004).

NF-KB mediates anti-oestrogen resistance through inhibition of the apoptotic pathway

Development of a various strategies to inhibit or prevent apoptosis is one of the most important hallmarks of cancer

(Hanahan & Weinberg 2011). The apoptotic machinery consists of both upstream regulators and downstream effectors (Wong 2011). The regulators are divided into two distinct molecular pathways: the intrinsic and extrinsic pathway (Wong 2011). The intrinsic or mitochondria-dependent pathway is activated by various types of intracellular signals and relies upon pro-apoptotic or anti-apoptotic molecules that are released from mitochondria such as cytochrome C, apoptosis-inducing factor, second mitochondria-derived activator of caspase (Smac), direct IAP-binding protein with low pI (DIABLO) and the Bcl-2 family of proteins, which are divided mainly into two groups, namely the pro-apoptotic proteins (e.g. BAX, BAK, BAD and BCLXs) and the anti-apoptotic proteins (e.g. BCL2, BCLXL and BCLW) (Wong 2011). The extrinsic pathway is activated by the binding of death ligands to their cell-surface death receptor such as the Fas receptor and the type 1 TNF receptor (TNFR1) (Wong 2011). Their ligands are called Fas ligand and TNF, respectively. The downstream effectors involve the activation of a series of caspases, including caspase 9 and caspase 8, which are the upstream caspases for the intrinsic and extrinsic pathway, respectively (Wong 2011). These two pathways converge on caspase 3, which then induces cleavage of many proteins such as protein kinases, DNA repair protein, cytoskeletal proteins and inhibitory subunits of the endonuclease family (Wong 2011). Following this step, the cell is progressively disassembled and then consumed by phagocytes (Wong 2011).

Increasing evidence reveals that NF-KB is involved in the apoptotic machinery through transcriptional dysregulation of pro-apoptotic or anti-apoptotic proteins such as TRAF proteins, the BCL2 family of proteins, p53 and inhibitor of apoptosis proteins (IAPs), resulting in reduced apoptosis and promoting survival in many cancers, including breast cancer (Baldwin 2001, Clarke et al. 2009, Schmitz et al. 2018). The following section will detail the major mechanisms that play a critical role in governing apoptosis via the NF-KB pathway.

NF-KB and ER synergistically enhance expression of the anti-apoptotic gene, BIRC3

Although much of literature has demonstrated trans-repression between ER and NF-KB, prominent positive crosstalk has also been identified via genome-wide transcriptional analysis of ER and NF-KB in hormone-positive breast cancer cell lines. Treatment with oestrogen enhances TNFα activity on nearly 15% of TNFα-upregulated genes, which includes Baculoviral IAP repeat containing 3

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(BIRC3)/cellular inhibitor of apoptosis protein 2 (cIAP-2) (Frasor et al. 2009). Importantly, treatment with oestrogen in combination with TNFα enhanced the upregulation of BIRC3 (Frasor et  al. 2009). BIRC3 is an important anti-apoptotic gene and is known to be upregulated by NF-KB in response to TNFα stimulation (Frasor et al. 2009). This finding suggests a synergistic role between ER and NF-KB in hormone-positive breast cancer that might promote an aggressive phenotype via activation of anti-apoptotic genes.

NF-KB inhibits mitochondrial membrane permeability, and reduces caspase-dependent apoptotic cell death through caspase 8 modulation and BCL2 expression

Evidence that confirms an anti-apoptotic role of NF-KB in endocrine therapy resistance is provided by a study using anti-oestrogen-resistant cells line (MCF7/RR and MCF7/LCC9), which demonstrates both high basal p65 expression and transcriptional activity of NF-KB compared with oestrogen-sensitive MCF-7 cells (Nehra et al. 2010). Inhibition of NF-KB, by either a small-molecule inhibitor of NF-KB or a mutant IκB (IκBSR), synergistically sensitizes both resistant cell lines to 4-hydroxytamoxifen (4HT), which leads to enhanced cancer cell apoptosis (Nehra et al. 2010). The study demonstrated that NF-KB inhibits apoptosis in resistant cells through increased BCL2 expression, which further alters the BCL2:BAX ratio, consequently inhibiting mitochondrial permeability to decrease cytochrome c excretion, resulting in inactivation of caspase activities and preventing apoptosis (Nehra et al. 2010). The study also reported that NF-KB inhibition restores 4HT activity to decrease BCL2 expression, increase mitochondrial permeability and apoptosis (Nehra et  al. 2010). Moreover, the study elucidated that caspase 8 inhibitors can restore all of these effects, indicating that NF-KB modulates caspase 8 activity to alter tamoxifen sensitivity. However, the precise mechanism is still uncleared and needs to be studied further.

NF-KB mediates anti-oestrogen resistance by blocking apoptosis and inhibiting autophagy through the XBP1-NF-KB signalling cascade

NF-KB is a crucial mediator for X-box binding protein 1 (XBP1) to drive the cell-fate decisions in breast cancer cells in response to anti-oestrogen therapy and subsequent development of anti-oestrogen therapeutic resistance (Hu et  al. 2015). XBP1 is a central effector in unfolded

protein responses that drive endoplasmic reticulum stress to maintain cell homeostasis (Tyson et  al. 2011). Overexpression of a spliced form, XBP1(S), in ER-positive breast cancer cells induces oestrogen-independent growth and resistance to anti-oestrogens (Gomez et  al. 2007, 2007). Addition of the NF-KB inhibitor parthenolide to 4-hydroxytamoxifen (4-OHT) strongly sensitized XBP1-overexpressing MCF-7 cells to 4-OHT. Similar to this result, p65 siRNA inhibited growth in XBP1 overexpressing MCF-7 cells (Gomez et  al. 2007). Furthermore, highly sensitivity to 4-OHT was found in p65-depleted XBP1-overexpressing MCF-7 cells (Gomez et  al. 2007). In addition, increase annexin V staining (apoptosis marker) and increased level of LC3II and p62 (autophagy marker) were observed in p65-depleted XBP1-overexpressing MCF-7 cells treated with 4-OHT, indicating that XBP1-NF-KB signalling mediates anti-oestrogen resistance through blocking apoptosis and autophagy (Gomez et al. 2007). Furthermore, the average tumour volume in XBP1-overexpressing xenografts treated with parthenolide were significantly less than those in the control group (Gomez et  al. 2007). These results strongly confirm that XBP1-mediated anti-oestrogen resistance is NF-KB dependent. However, the mechanism that is accountable for the XBP1 regulation of p65/RelA remains unknown.

NF-KB prevents immune surveillance in endocrine-resistant breast cancer

Programmed cell death ligand 1 (PD-L1) frequently expressed in various types of solid tumour engages with programmed cell death 1 (PD-1) on immune cells and is considered a crucial contributor in cancer immune evasion (Zhang et al. 2018) that might lead to resistance of treatment.

The role of NF-KB in PD-L1 expression was demonstrated by using siRNA-mediated silencing of p65 and p50 led to a decrease in the IFN-γ-induced expression of PD-L1 in melanoma cell lines (Gowrishankar et  al. 2015). In addition, transfected melanoma cells with the mutant IκB-GFP plasmid that lack the phosphorylation site, which is required for proteasomal degradation, following with IFN-γ treatment resulted in a decrease in expression of PD-L1. This result suggest NF-KB is required for expression of PD-L1 (Gowrishankar et al. 2015).

Increasing evidence has demonstrated different biochemical aspects of PD-L1 regulation, including epigenetic modification, transcriptional regulation and

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post-translational modification (Zhang et  al. 2018). The COP9 signalosome 5 (CSN5), known as deubiquitinating enzymes (DUBs) has been demonstrated to stabilize PD-L1 at the post-transcriptional level, which results in suppression of immune surveillance (Lim et  al. 2016). Recently, it has been shown that upon TNF-α stimulation, the NFκB p65 subunit binds to the CSN5 promoter to promote its transcription, which subsequently induces its binding to PD-L1 to further deubiquitinate and stabilize the protein (Lim et al. 2016).

Using the ENCODE database of transcription factors, it was shown that p65 directly interacts with CSN5 promoter region and promotes its transcription in response to TNF-α treatment (Lim et al. 2016). CSN5 expression was reduced in shRNA p65 knockdown cells, suggesting p65 is required for CSN5 transcription. Increased expression of PD-L1 was found in TNFα-treated shCTRL cell, whereas the expression was abolished in TNFα-treated shCSN5 cells, indicating CSN5 as a crucial factor to stabilize PD-L1 (Lim et al. 2016). Moreover, in patient samples, it was shown that there was positive correlation between CSN5 and PD-L1 expression, with high CSN5 expression significantly associated with short overall survival (Lim et al. 2016). In addition, high expression of CSN5 and p65 were associated with poor recurrence-free survival (Lim et al. 2016). These findings suggest the NF-KB p65 subunit as a crucial transcription factor, which is required for CSN5 transcription, and TNFα-mediated PD-L1 stabilization, resulting in suppressed T cell function. According to these finding, reduced PD-L1 stability, which will further allow PD-L1 poly-ubiquitination and subsequent degradation through the inhibition of TNF-α/p65/CSN5/PD-L1 axis represent a potential target to restore treatment sensitivity in breast cancer cells.

PD-L1 expression was upregulated nearly 40% of basal subtype breast cancer, and high PD-L1 expression was associated with poor clinical features such as high grade, high proliferation, ER-negative and HER2-enriched subtypes (Sabatier et al. 2015). Importantly, combination of anti-PD-L1 and nab-paclitaxel was recently approved for patient with unresectable locally advanced or metastatic TNBC who is tumour positive for PD-L1 (Schmid et  al. 2018).

Although PD-L1 upregulation is not widely reported in ER-positive breast cancer, up to 20% of primary breast cancer with luminal B subtype have been demonstrated to overexpress PD-L1 (Muenst et  al. 2014). In addition, expression of PD-L1 was found 68% in circulating breast cancer cells from metastatic ER-positive HER2-negative breast cancer, indicating increased expression of PD-L1

alongside with disease progression (Mazel et  al. 2015). Furthermore, in univariate analysis, the expression of PD-L1 was associated with decreased overall survival in patients with luminal B subtype (P < 0.0001) (Muenst et  al. 2014). Recently, a basket study of single agent pembrolizumab in patient with PD-L1-positive solid tumours, which had a cohort of patient with ER-positive/HER-2-negative breast cancer demonstrated modest but durable overall response in patient with ER-positive, HER-2-negative breast cancer (Rugo et al. 2018).

Collectively, PD-L1 expression is more frequently demonstrated in breast cancer that exhibit inflamed phenotype such as TNBC as well as in patients with metastatic ER-positive disease. Therefore, combination checkpoint inhibitor with standard treatment might be beneficial for patients with high immune response metastatic ER-positive breast cancer.

NF-KB influence the cell cycle in endocrine therapy resistance

Dysregulation of the cyclin D–CDK 4/6–INK4–retino-blastoma (Rb) pathway regulates proliferation in breast cancer and is a key contributor to hormone therapy resistance (Spring et  al. 2016). Activation of the cyclin D1/CDK4/6 complex induces phosphorylation of the Rb protein, followed by destabilization of its interaction with E2F transcription factors, resulting in E2F enhanced transcription of genes that promote cell cycle progression (Lange & Yee 2011). Multiple mitogenic signalling pathways have been demonstrated to influence the increasing of the expression of cyclin D1, including PI3K/AKT/mTOR, MAPKs, STATs, ER and NF-KB pathways (Lange & Yee 2011).

IKKα phosphorylates both ER and SRC3 to further increase their activity regarding cell cycle regulation

As previously described, oestrogen induces the formation of the IKKα, ER and steroid receptor co-activator (SRC) 3 complex on the promoter region of CYCLIN D1 gene. IKKα is also able to phosphorylate both ER and SRC3 to further increase their transcription activity (Park et  al. 2005, Park 2017). In addition, IKKα has been reported as a key kinase in response to oestrogen-induced E2F1 expression. IKKα siRNA treatment in MCF7 cells leads to a dramatic decrease in the expression of E2F1-regulated genes that are crucial for S phase entry, including TK1, PCNA, CDC25A and CYCLIN E (Tu et al. 2006). IKKα knocked-in cells also induce upregulation of E2F1 expression (Tu et al. 2006).

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Although the mechanism of how IKKα regulates E2F1 is not clear, previous data suggests that IKKα may interact with p300/CBP-associated factor (PCAF), which is a potent enzyme that can acetylate E2F1 (Martinez-Balbas et  al. 2000). A previous study demonstrated a nuclear role of IKKα that may activate the expression of NF-KB-responsive genes upon activation of cytokines through phosphorylation of histone H3. In response to TNFα activation, IKKα forms a complex with p65 and the co-activator of cAMP-response element-binding protein to further acetylate-specific residues on histone H3 leading to increased gene expression (Yamamoto et  al. 2003). Therefore, it may be suggested that IKKα associates with PCAF to acetylate E2F1 in response to oestrogen-induced E2F1 expression. Collectively, this evidence confirms that NF-KB and its kinase influence hormone resistance in breast cancer by affecting cyclin D and E2F to promote cell cycle progression. Aberrant IKKα/NF-KB signalling might lead to dysregulation of CYCLIN D1 and E2F1, resulting in the persistent activity of cell cycle machinery that can promote breast cancer cell growth and resistance to treatment.

NF-KB and growth factor signalling in response to endocrine resistance

NF-KB and EGF pathway

Patients with ER+/HER2+ metastatic breast cancer benefit less from endocrine therapy, compared to those with ER+/HER2- disease (Ballinger et al. 2018). Importantly, a significant amount of evidence has established the EGF

pathway is involved in endocrine resistance (Montemurro et al. 2013). Binding to EGF induces a kinase activity of the homo- and heterodimers of EGFRs, leading to auto-phosphorylation of these receptors and further activation of downstream signalling. As a consequence of EGFR activation, several signalling pathways are activated, including the PI3K/Akt/mTOR pathway to control cell proliferation, and the RAS/RAF/MEK/ERK to control cell survival and progression. Crosstalk between growth factor signalling and ER has long been established. A small amount of ER localizes at the membrane (mbER) and interacts with other proteins, including SRC and PI3K to from the mbER complex. Upon binding to oestrogen, the mbER complex can induce the PI3K/AKT/mTOR pathway by enhancing the tyrosine kinase activity of EGFR and activates mTOR by PI3K-mediated AKT phosphorylation. Moreover, phosphorylated AKT can phosphorylate both ligand-dependent and non-ligand-dependent ER. Collectively, crosstalk between these pathways induces endocrine resistance both to tamoxifen and AI.

In contrast to ER-negative breast cancer, there is some evidence to provide a connection between HER2 and NF-KB pathway in ER-positive MCF-7 cells. In response to ionizing radiation, overexpression of HER2 activates the PI3K/AKT pathway, which then promotes NF-KB activation, resulting in upregulation of several pro-survival genes such as a mitochondrial antioxidant enzyme manganese superoxide dismutase, cyclin B1 and HER-2 itself. Consequently, MCF-7/HER-2 cells came to be both radio- and chemo-resistant (Pianetti et  al. 2001). Given the role of NF-KB as a downstream effector of HER2/PI3K/AKT cascade, it might be possible that mbER indirectly

Figure 3Alternative approaches to target NF-KB pathway. (A)Targeting BCR-induced NF-KB signalling using inhibitors of Burton tyrosine kinase (BTK) such as Ibrutinib, results in inhibition of NF-KB downstream signalling. (B) Targeting IKKγ or NEMO using NEMO-ubiquitin interaction inhibitors (iNUBs). (C) Targeting IκBα degradation using proteasome inhibitors such as botezomib. (D) Targeting IKKs using selective IKKα or IKKβ inhibitors. (E) Targeting NIK using small-molecule inhibitors. (F) Targeting NF-KB activity, including inhibition of nuclear translocation, dimerization and DNA binding. A full colour version of this figure is available at https://doi.org/10.1530/ERC-19-0087.

LTβR, CD 40

LT, CD 40L

p100RelBp65 p50

IKKγ

TAK1

Pp

IκBα

TNFα

p65 p50

IKKβIKKα

Ub

TNFR

p100

NIK

Pp

IKKα IKKα

RelB

Ub

p pp p

NF-kB target gene

Targeting NIK

Targeting IκBαdegradation

Targeting nuclearlocalization,

dimerization and DNAbinding ofNF-kB

BCRTargeting upstreamcompounds:Ibrutinib

Targeting IKKγ/NEMO: iNUBs Targeting

IKKα or IKKβ

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affects NF-KB through the activation of HER2/PI3K/AKT. However, this hypothesis requires further investigation.

Specific NF-KB inhibition: a novel strategy to overcome endocrine therapy resistance

The potential role of NF-KB as a target for endocrine therapy resistance in breast cancer has recently been highlighted leading to the development of inhibitors to target the NF-KB pathway; however, this is very much still in the development stage. To date, different NF-KB inhibitors have been experimentally identified and provide sophisticated result (Herrington et al. 2016, Paul et  al. 2018). These vary from broad-spectrum inhibitor of NF-KB, including anti-inflammatory agents such as glucocorticoids, non-steroidal anti-inflammatory drugs, to those that selectively inhibit each step of the pathway, including inhibition of NF-KB nuclear translocation, inhibitor of IκB function such as proteasome inhibitor, inhibition of IκB proteins phosphorylation (parthenolide, flavopyridol) and inhibitor of IKKs (IKKα and IKKβ). Currently, selective inhibitors of IKKβ have been extensively studied and demonstrated promising outcome in pre-clinical models in cancer; however, they still lack clinical success due to severe on-target toxicities (Prescott & Cook 2018). Among other novel drugs, only proteasome inhibitors, bortezomib and carfizomib, have received recent Food and Drug Administration approval for the treatment of refractory multiple myeloma (Herndon et  al. 2013). As discussed, multiple upstream activators and downstream effectors modulate NF-KB signalling; therefore, targeting alternative factors in the pathway might be a successful strategy (Fig. 3).

Conclusion and future perspective

Endocrine resistance remains an important issue in clinical practice for breast cancer care. NF-KB has been confirmed to be a crucial link between the resistance signalling pathways, leading to endocrine therapy failure. However, given the fact that breast cancer is a heterogeneous disease and the complexity of endocrine resistance mechanism, which can influence the interaction between NF-KB and ER in difference levels, more work is still needed. Future research should integrate ‘omic’ platforms in order to understanding the precise mechanism of how these two transcription factors interact with each other and

influence endocrine resistance. In addition, focussing on individual NF-KB subunit in response to distinct upstream or downstream factors in resistance setting might help researchers to identify a key target in order to restore endocrine sensitivity.

Declaration of interestThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

FundingThis work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

AcknowledgementsAll authors have read the journal’s policy on disclosure of potential conflicts of interest and have none to declare.

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Received in final form 28 March 2019Accepted 4 April 2019Accepted Preprint published online 4 April 2019

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