58 3 T B DOAN and others Nuclear receptors in 58: 3 R169–R190 Review breast cancer Emerging functional roles of nuclear receptors in breast cancer Tram B Doan, J Dinny Graham and Christine L Clarke Correspondence should be addressed Westmead Institute for Medical Research, Sydney Medical School – Westmead, University of Sydney, to T B Doan Sydney, New South Wales, Australia Email [email protected] Abstract Nuclear receptors (NRs) have been targets of intensive drug development for decades Key Words due to their roles as key regulators of multiple developmental, physiological and disease f nuclear receptors processes. In breast cancer, expression of the estrogen and progesterone receptor remains f breast cancer clinically important in predicting prognosis and determining therapeutic strategies. f circadian clock More recently, there is growing evidence supporting the involvement of multiple nuclear f metabolism receptors other than the estrogen and progesterone receptors, in the regulation of f migration and metastasis various processes important to the initiation and progression of breast cancer. We review new insights into the mechanisms of action of NRs made possible by recent advances in genomic technologies and focus on the emerging functional roles of NRs in breast cancer biology, including their involvement in circadian regulation, metabolic reprogramming Journal of Molecular and breast cancer migration and metastasis. Endocrinology (2017) 58, R169–R190 Journal of Molecular Endocrinology Introduction Breast cancer is the most common cancer diagnosed nearly all physiological aspects of life and the availability in women worldwide (Ferlay et al. 2015). Over the past of drugs targeting NRs that resulted from intensive drug decades, substantial progress toward treatment of primary development targeting NRs for a range of pathological estrogen receptor-positive (ER+) breast cancer has been conditions. The human NR superfamily consists of 48 made with the development of endocrine therapies highly evolutionarily conserved transcription factors with targeting the estrogen biosynthesis and signaling the ability to act as molecular sensors of physiological pathways. Despite the success of endocrine therapies, and environmental stimuli (Mangelsdorf et al. 1995). there remain subgroups of women for whom available Development of technologies that allow genome-wide, treatment offers little help. These include patients with unbiased profiling of genomic binding sites and gene ER+ breast tumors who develop endocrine treatment expression has allowed deeper insights into the molecular resistance (Dixon 2014), patients with estrogen receptor- mechanisms of NR actions. These studies highlight the negative (ER−) breast cancers (Hudis & Gianni 2011) complexity of gene regulatory networks governed by and cancers that recur in all age groups (EBCTCG 2005). NRs, the extensive nature of NR crosstalk and the role Women in these subgroups currently face the challenge of coregulators and the chromatin landscape of the cell of living with advanced disease; therefore, there exists as important modulators of NR cell type-specific and the need to develop rational treatments targeting these context-dependent function. subgroups of breast cancer. In the context of breast cancer, it is recognized that Nuclear receptors (NRs) are potential promising targets estrogen receptor (ESR1) and progesterone receptor (PGR) due to the importance of NRs as master regulators of play critical roles in the development and progression http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-16-0082 Printed in Great Britain Downloaded from Bioscientifica.com at 09/27/2021 09:55:09AM via free access 10.1530/JME-16-0082 Review T B DOAN and others Nuclear receptors in 58:3 170 breast cancer of breast cancer, and moreover, their expression in a two zinc finger motifs which confers response element breast tumor remains the single most robust predictor of specificity and the hinge region linking the DBD to the disease outcome. Consequently, measurement of ESR1 ligand-binding domain (LBD), which may or may not and PGR expression in breast cancers is a mainstay of have an AF2 region that mediates coactivator interaction clinical management programs and treatments targeting (Giguere et al. 1986, Kumar et al. 1987, Mangelsdorf et al. the estrogen signaling axis are standard of care for ER+ 1995) (Fig. 1A). Approximately half of the NRs are disease (Cordera & Jordan 2006). More recently, the designated as orphans because endogenous physiological androgen receptor (AR), which is frequently expressed ligands for these NRs have not been found (Table 1). The in primary breast tumors (Park et al. 2010, Grogg et al. 48 human NRs are organized into six evolutionary groups 2015), has emerged both as a marker of outcome and based on sequence alignment and phylogenetic tree as a potential treatment target (Cordera & Jordan 2006, construction (Auwerx et al. 1999, Germain et al. 2006). Barton et al. 2015). A number of other nuclear receptors, Organization of NRs into functional groupings is also including the vitamin D3 receptor (VDR) (Krishnan et al. feasible, based on profiling the anatomical expression of 2010, Mehta et al. 2013) and the glucocorticoid receptor NRs. In the mouse, this revealed a hierarchical organization (GR) (Vilasco et al. 2011, Abduljabbar et al. 2015b) of NRs into integrated physiologic functional groups have also been investigated for their anti-proliferative (Fig. 1B), which partially reflect the functional groupings and anti-apoptotic effects in breast cancer. Members observed in human, especially for NRs that are involved of the retinoid receptor subfamily have also received in circadian and metabolic pathways (reviewed here). considerable attention, particularly the crosstalk between In the classical model of NR action, upon ligand the retinoic acid receptor alpha (RARA) and estrogen activation, NRs regulate gene transcription by binding signaling (Hua et al. 2009, Ross-Innes et al. 2010), and response elements within the regulatory regions of target the anti-migratory effect of the retinoic acid receptor beta genes as monomers, homodimers or heterodimers with (RARB) in breast cancer (Yang et al. 2002, Flamini et al. another family member. For example, steroid hormone 2014). However, the functional roles of the majority receptors generally bind as homodimers, whereas VDR, of the remaining members of the human NR family in THR, RAR and RXR can form both homodimers and the normal breast and breast cancer have largely been heterodimers. RXRs in particular can act as promiscuous unexplored. Recent studies are establishing that the heterodimerization partners for VDR, THR, RAR and involvement of NRs in breast cancer extends beyond their orphan receptors. Dimerization is a general mechanism involvement in regulating proliferation and apoptosis to increase binding affinity, specificity and diversity. Journal of Molecular Endocrinology and that NRs are important regulators of several aspects Nuclear receptor response elements are derivatives of the of breast cancer tumorigenesis and progression including canonical hexameric sequence RGGTCA. Modifications regulation of the circadian clock, metabolism, migration and duplications (organized as direct, inverted or everted and metastasis. In this review, we will discuss evidence for repeats separated by a spacer with variable length) of these emerging functional roles of NRs in breast cancer, this canonical hormone response element allow for as well as new insights into the molecular mechanisms selective recognition by different NR subclasses (Laudet & of action of NRs made possible through advances in Gronemeyer 2002, Gronemeyer et al. 2004). genomic technologies. Ligand binding also allosterically controls the interaction of NRs with coregulators by influencing the conformation of the AF2 region. Coregulators are integral The nuclear receptor superfamily to the mechanisms by which NRs exert their functions The human nuclear receptor superfamily consists of 48 and include both coactivators and corepressors. The members. These transcription factors include the receptors majority of coregulators function as members of large for steroid hormones, thyroid hormones, lipophilic complexes that affect NR transcriptional regulation of vitamins and cholesterol metabolites including retinoic target genes through interactions with other transcription acid and oxysterols (Mangelsdorf et al. 1995). Members factors, the chromatin landscape as well as non-coding of the NR superfamily are identified through their highly RNAs (Millard et al. 2013). Both the interaction with evolutionarily conserved structural organization (Evans & coregulators and the chromatin landscape of the cell have Mangelsdorf 2014), which consists of four major domains: been shown to affect the cell type specificity of NRs. The N-terminal A/B domain with activation function1 NRs regulate the transcription of genes that control a (AF1); the DNA-binding domain (DBD) consisting of wide variety of biological processes in normal physiology http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-16-0082 Printed in Great Britain Downloaded from Bioscientifica.com at 09/27/2021 09:55:09AM via free access PROOF ONLY Review T B DOAN and others Nuclear receptors in 58:3 171 breast cancer Figure 1 (A) Schematic diagram of the structural and functional