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The NF-KB Pathway and Endocrine Therapy Resistance in Breast Cancer

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The NF-KB Pathway and Endocrine Therapy Resistance in Breast Cancer 26 6 Endocrine-Related P Khongthong et al. Nuclear factor kappa B and 26:6 R369–R380 Cancer breast cancer 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: [email protected] Abstract Breast cancer is a heterogeneous disease, which over time acquires various adaptive Key Words changes leading to more aggressive biological characteristics and development of f NF-KB treatment resistance. Several mechanisms of resistance have been established; however, f endocrine therapy due to the complexity of oestrogen receptor (ER) signalling and its crosstalk with other resistance signalling networks, various areas still need to be investigated. This article focusses f breast cancer 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. Endocrine-Related Cancer (2019) 26, R369–R380 Introduction Oestrogen receptor α-positive (ER+) breast cancer respond to endocrine therapies as a result of either de constitutes more than 70% of all breast cancers novo or acquired resistance (Liu et al. 2017). (Cardoso et al. 2012). Both early and metastatic disease Many comprehensive reviews (Riggins et al. 2007, are treated effectively with endocrine therapies, which Clarke et al. 2009, Zhao & Ramaswamy 2014, Liu et al. downregulate oestrogen receptor (ER) signalling, leading 2017, AlFakeeh & Brezden-Masley 2018, Masuda et al. to tumour growth inhibition (Cardoso et al. 2012). The 2018) summarize the mechanisms of endocrine therapy three main groups of endocrine therapy are selective resistance, including (i) the loss of ER expression or oestrogen receptor modulators, including tamoxifen mutation of the ER that causes constitutive activation and raloxifene, which acts as an oestrogen antagonist regardless of oestrogen; (ii) the amplification and to bind to ER and further recruit transcriptional upregulation of ER co-activators such as amplified co-repressor instead of co-activators, leading to in breast 1 (AIB1, also known as steroid receptor inhibition of tumour growth (Legha 1988); selective co-activator-3 (SRC3)), that can increase the activity oestrogen receptor downregulators (SERDs), including of ERs; (iii) the upregulation of alternative oncogenic fulvestrant, which prevents ER dimerization and induce pathways such as phosphatidylinositol 3-kinase/a serine- its degradation (Wardell et al. 2011); and aromatase threonine-specific protein kinase/mammalian target inhibitors (AIs), including anastrozole, letrozole and of rapamycin (PI3K/AKT/mTOR) pathway resulting in exemestane, which inhibit the enzyme aromatase increased activity of protein kinase pathways; (iv) the resulting in reduction of oestrogen levels through the amplification and overexpression of gene regions that blockade of testosterone conversion to oestrogens both encode oncogenic proteins and transcription factors to in the tumour and peripheral tissue (Baum et al. 2003). promote cancer cell survival, invasion and metastasis; However, a significant number of the patient fail to and (v) the deregulation of the proteins that control cell https://erc.bioscientifica.com © 2019 Society for Endocrinology https://doi.org/10.1530/ERC-19-0087 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/29/2021 03:05:57PM via free access -19-0087 Endocrine-Related P Khongthong et al. Nuclear factor kappa B and 26:6 R370 Cancer breast cancer cycle machinery such as the cyclin-dependent kinases their target genes through the recruitment of co-activators (CDKs), resulting in dysregulated cellular proliferation. and co-repressors (Zhang et al. 2017). The potent Among these mechanisms, mTOR deregulation is transcription activation domain (TAD) is found only in considered clinically relevant and the mTOR inhibitor p65, c-Rel and RelB. Due to the lack of TADs, dimers of everolimus plus exemestane is included as an option for p50 or p52 may mediate only transcriptional repression ER-positive advanced disease; however, this combination (Zhang et al. 2017). failed to improve overall survival in clinical trials (Baselga In unstimulated cells, homo- or heterodimers of et al. 2012). In addition, due to double improvement in NF-KB are bound to their inhibitors and the IκB proteins progression-free survival, palbociclib, a highly selective are sequestered in the cytoplasm (Zhang et al. 2017). inhibitor of CDK4/6 kinases, in combination with Upon activation, NF-KB translocates to the nucleus letrozole had recently approved as first-line endocrine to interact with κB site to induce transcription of the therapy for postmenopausal ER-positive, HER2-negative target genes (Zhang et al. 2017). The most frequently advance breast cancer (Finn et al. 2015). Despite the recent recognized NF-KB pathways are the canonical and non- advances in therapeutic approach, metastatic breast canonical pathway (Zhang et al. 2017). The canonical cancer is incurable, and finally will develop treatment NF-KB pathway is activated by pro-inflammatory resistance, further increasing the complexity of molecular cytokines such as TNF-α and interleukin-1 (IL-1), interactions. Therefore, identifying the novel driving T- and B-cell mitogens, bacterial liposaccharide (LPS), factors that modulate oestrogen signalling and other viral proteins, and physical and chemical stress important pathways still need to be addressed. (Karin & Ben-Neriah 2000, Hoesel & Schmid 2013) (Fig. 1). Nuclear factor kappa B (NF-KB) is a key transcription A first step in the canonical pathway is the activation factor that links inflammation with cancer and is of transforming growth factor-β (TGF-β)-activated kinase demonstrated as being involved in the tumorigenesis of 1 (TAK1), which further activates a trimeric IkB kinase breast cancer and endocrine therapy resistance. However, (IKK) complex that is composed of regulatory (NF-KB the molecular mechanisms of how NF-KB contributes to essential modulator (NEMO or IKKγ)) and catalytic (IKKα endocrine therapy resistance are still unclear. This article and IKKβ) subunits (Zhang et al. 2017). The IKK complex will summarize the currently available evidence that then phosphorylates IκB at specific serine residues, supports the promising role of NF-KB pathway in the which results in polyubiquitination and subsequent mechanism of endocrine therapy resistance, in order to proteasomal degradation of IκB, followed by nuclear elucidate NF-KB as a potential novel target for overcoming translocation of NF-KB, mainly the p50/p65 heterodimer this resistance. (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, NF-KB signalling adhesion molecules and apoptosis inhibitors (Hoesel The NF-KB family of inducible transcription factors are & Schmid 2013, Lim et al. 2016, Zhang et al. 2017). composed of five members, including p50, p52, p65 In contrast to the canonical pathway that responds (RelA), RelB and c-Rel, all of which share an N-terminal rapidly to signals from the diverse receptors, the non- Rel homology domain (RHD) (Zhang et al. 2017). RHD canonical pathway specifically responds to a small group contains a nuclear localization sequence, and is responsible of receptors, including lymphotoxin-β receptor (LTβR), for sequence-specific DNA binding, dimerization and B-cell activating factor belonging to TNF family receptor interaction with ankyrin repeat motifs, which are (BAFFR), CD40 and receptor activator for NF-KB (RANK), present in IκB inhibitory proteins (Zhang et al. 2017). as summarized in recent comprehensive review (Sun The ‘inhibitor of κB’ (IκB) proteins include IκBα, IκBβ, 2012, 2017). Upon binding to its specific ligand, these IκBγ, IκBϵ, BcL-3, the precursors p105 and p100, and the receptors activate the kinase NF-KB-inducing kinase Drosophila protein Cactus (Zhang et al. 2017). Among (NIK), which, in turn, phosphorylates and activates them, IκBα, IκBβ and IκBϵ are the most important IKKα. Activated IKKα then phosphorylates p100/RelB regulators of NF-KB. NF-KB dimers bind to κB sites within heterodimer at the carboxyterminal serine residues of the promoters or enhancers of target genes, which bare p100, subsequent to proteasomal degradation of the C- 5’-GGGRNWYYCC-3’ (N, any base; R, purine; W, adenine terminal IκB-like structure of p100, resulting in processing or thymine; Y, pyrimidine), and regulate transcription of of p100 to p52 and nuclear translocation of p52/RelB https://erc.bioscientifica.com © 2019 Society for Endocrinology https://doi.org/10.1530/ERC-19-0087 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/29/2021 03:05:57PM via free access Endocrine-Related P Khongthong et al. Nuclear factor kappa B and 26:6 R371 Cancer breast cancer CanonicalNF-kB pathwayNon-canonicalNF-kB pathway TNFα, IL1 LT,CD40L BCR TNFR LTβR,CD40 Cytoplasm TAK1 NIK Figure 1 IKKγ p The NF-KB pathway. The canonical pathway is p P P IKKα IKKα IKKα IKKβ induced by TNFα, IL1 and various other stimuli,
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