The Impact of Transcription on Metabolism in Prostate and Breast Cancers

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Endocrine-Related N Poulose et al. From hormones to fats and 25:9 R435–R452 Cancer back

REVIEW The impact of transcription on metabolism in prostate and breast cancers

Ninu Poulose1, Ian G Mills1,2,* and Rebecca E Steele1,*

1Centre for Cancer Research and Cell Biology, Queen’s University of Belfast, Belfast, UK 2Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, UK

Correspondence should be addressed to I G Mills: [email protected]

*(I G Mills and R E Steele contributed equally to this work)

Abstract

Metabolic dysregulation is regarded as an important driver in cancer development and Key Words progression. The impact of transcriptional changes on metabolism has been intensively ff androgen studied in hormone-dependent cancers, and in particular, in prostate and breast cancer. ff androgen receptor These cancers have strong similarities in the function of important transcriptional ff breast drivers, such as the oestrogen and androgen receptors, at the level of dietary risk and ff oestrogen epidemiology, genetics and therapeutically. In this review, we will focus on the function ff endocrine therapy of these nuclear hormone receptors and their downstream impact on metabolism, with a resistance particular focus on lipid metabolism. We go on to discuss how lipid metabolism remains dysregulated as the cancers progress. We conclude by discussing the opportunities that this presents for drug repurposing, imaging and the development and testing of new Endocrine-Related Cancer therapeutics and treatment combinations. (2018) 25, R435–R452

Introduction: prostate and breast cancer

Sex hormones act through nuclear hormone receptors Early-stage PCa is dependent on androgens for survival and induce distinct transcriptional programmes essential and can be treated by androgen deprivation therapy; to male and female physiology. They exert their effects however, with the advancement of cancer, it becomes on target tissues such as the mammary gland, ovary and refractory to hormone treatment. This later stage of PCa the uterus in females and the testis and the prostate is known as castrate-resistant PCa (CRPC) or androgen- gland in males. Studies indicate that these hormones indifferent PCa, meaning that the cancer thrives despite a also play pivotal roles in the development of endocrine- reduction in serum androgen levels (Feldman & Feldman related cancers. The highest incidence cancers affecting 2001, Beltran et al. 2011). The prostate is also a target for hormone-dependent organs are prostate cancer (PCa) oestrogens among which oestradiol-17β is considered and breast cancer (BCa). PCa is the second most common the most potent inducer of prostatic proliferation and male malignancy in many western industrialised promotes epithelial-to-mesenchymal transition in countries and fifth leading cause of cancer death in men benign prostatic epithelial cells (Shi et al. 2017). Studies worldwide (GLOBOCAN 2012). BCa is the most frequently also suggest that oestrogen–androgen balance may be a diagnosed female malignancy and the fifth most common key determinant in the development of aggressive PCa cause of death from cancer overall (GLOBOCAN 2012). (Black et al. 2014). Likewise androgens play important

-18-0048 Endocrine-Related N Poulose et al. From hormones to fats and 25:9 R436 Cancer back roles in the development and progression of BCa subtypes tissues bound to serum sex hormone-binding globulin such as molecular apocrine tumours (Robinson et al. and albumin, where it is converted to the more active 2011). Endogenous oestrogen levels have been linked metabolite, DHT by the enzyme 5α-reductase (Heinlein & to an increased risk of breast and endometrial cancers Chang 2004, Eacker et al. 2008). (Brown & Hankinson 2015). AR also known as NR3C4 (nuclear receptor subfamily The predominant BCa subtype is luminal tumours, 3, group C, member 4) is a ligand-dependent TF that accounting for approximately two-thirds of all diagnosed regulates the expression of genes involved in male BCa cases (Ignatiadis & Sotiriou 2013). Originating from sexual phenotype. AR gene encodes a protein of 110 KDa breast luminal epithelial cells, the majority of luminal with three major domains, the N-terminal domain, tumours are oestrogen receptor (ER) positive, and clinical the DNA-binding domain and the C-terminal ligand- studies have highlighted a strong ovarian-derived steroid binding domain (LBD). Binding of androgens to LBD hormone-driven biology, in mammary gland tumour causes dissociation of heat shock proteins, its nuclear development, particularly associated with oestradiol- translocation through binding of importin-α, subsequent 17β (Pike et al. 1993, Perou et al. 2000). ER-positive BCa dimerisation and binding to androgen response elements patients have the most favourable BCa subtype prognosis, in the promoter regions of target genes, such as prostate- generally responding well to endocrine-targeted therapies; specific antigen (PSA) and transmembrane protease serine however, endocrine therapy resistance does occur (García- 2 (Tan et al. 2015). AR is expressed mostly in the secretory Becerra et al. 2013). In recent years, an important role for epithelial cells and to some extent in the stroma, whereas the androgen receptor (AR) in breast tumourigenesis has basal cells are AR negative (Prins et al. 1991). In a fully emerged, with between 70 and 90% of tumours shown to formed prostate, the androgens continue to function to harbour AR positivity (Moinfar et al. 2003, Niemeier et al. promote the survival of secretory epithelia. Physiological 2010, Collins et al. 2011). In addition, two gene expression testosterone and DHT levels prevented apoptosis in these studies have identified an AR-positive BCa subtype; secretory epithelial cells, whereas castration resulted in a molecular apocrine BCa tumours, also characterised by loss of prostate secretory epithelial cells due to apoptosis ER negativity, they constitute 8–12% of all BCa cases in rat models, which was preceded by degeneration of (Farmer et al. 2005, Doane et al. 2006). Despite their prostatic capillaries (Heinlein & Chang 2004). Hence, ER-negative status, molecular apocrine tumours express a AR signalling remains essential to the structural and number of genes that are usually expressed in ER-positive functional integrity of prostate gland. tumours such as XBP-1, SCUBE2, SPDEF and FOXA1 ER signalling is important for a number of normal (Doane et al. 2006, Robinson et al. 2011). It is proposed cellular proliferative processes and the maintenance of that in such tumours, in the absence of ER, AR can bind to lipid and carbohydrate metabolic homeostasis, primarily ER cis-regulatory genomic elements and transcriptionally in reproduction-related tissues (Nilsson & Gustafsson activate canonical ER target genes (Robinson et al. 2011). 2011, Vrtačnik et al. 2014). In addition, the role of Consequently, patients with molecular apocrine tumours the ER in both BCa and PCa development has been display poor clinical response to ER antagonists, and extensively studied. Like testosterone, oestrogen is a it is believed that the use of anti-androgens may be of steroid hormone, derived from cholesterol; it mediates increasing therapeutic benefit Farmer( et al. 2005). its function through binding to one of two cognate ERs – alpha (ERα) and beta (ERβ). Two ERα isoforms ERα36 (Wang et al. 2005) and ER 46 (Flouriot et al. 2000) Nuclear hormone receptors – AR and ER α have additionally been identified. Although there are Nuclear hormone receptors such as the AR and ER are two subtypes, ERα is the main driver in ER-positive ligand-activated transcription factors (TFs), which induce BCa and the main subtype of focus in this review. distinct transcriptional programmes conducive to the Upon ligand activation, ERα dimerises and interacts development and differentiation of prostate and breast with transcriptional coregulators to bind to oestrogen- tissues, respectively. The growth and maintenance of responsive elements upstream of ERα target genes (May the prostate is dependent on androgens, testosterone & Westley 1988, Hayashi et al. 2003). ERα is primarily and 5α-dihydrotestosterone (DHT), acting through expressed in the mammary gland and is a ligand- their cognate receptor, AR (Heinlein & Chang 2004). inducible TF and signal transducer that has functional Testosterone is synthesised from cholesterol, primarily by roles in proliferation, differentiation and migration and the Leydig cells in the testes and transported to the target is known to transcriptionally regulate genes involved

Figure 1 Schematic diagram showing the metabolic landscape in (A) the normal prostate gland and (B) prostate cancer. ACLY, ATP citrate lyase; ACON, aconitase; CS, citrate synthase; EAAC1, excitatory amino acid carrier 1; MAAT, aspartate aminotransferase; PDH, pyruvate dehydrogenase. Pathways are shown in black arrows and inhibitory steps in red lines.

(Costello & Franklin 2006). The active transport of zinc accumulation (Costello & Franklin 2006, Makhov et al. in prostate cells is mainly mediated through SLC39A1 2011). Interestingly, the expression of ZIP1 and ZIP2 or ZIP1. The continued supply of acetyl CoA and OAA are comparatively lower in normal prostate tissue from for citrate production are met by a high rate of aerobic African-Americans patients who are at a higher risk of glycolysis and aspartate accumulation, respectively. PCa incidence when compared to age-matched Caucasian Glycolysis converts glucose to pyruvate, which enters men (Rishi et al. 2003). Epigenetic changes especially mitochondria and gets decarboxylated to acetyl CoA by methylation is one of the most recurrent events in locally pyruvate dehydrogenase (PDH). OAA is produced from the advanced and metastatic PCa with AR promoter CpG transamination of aspartate, which is actively transported islands reported to be hotspots of aberrant methylation into the prostate cells through the specific receptor and consequent loss of AR expression (Kinoshita et al. 2000, excitatory amino acid carrier 1 (EAAC1) (Franklin et al. Massie et al. 2017). DNA methylation is intimately linked 2006). Testosterone stimulates the expression/activity of to central metabolism as well as one carbon metabolism. EAAC1, aspartate aminotransferase and mitochondrial Androgens regulate the expression of key biosynthetic PDH thus facilitating citrate production by regulating enzymes involved in the polyamine synthesis in the both acetyl CoA and OAA levels (Franklin et al. 1986, 2006, prostate, which requires one carbon metabolism and Costello & Franklin 1993). In addition, testosterone affects share the DNA methylation donor, S-adenosylmethionine citrate oxidation by differentially regulating m-aconitase (SAM). Therefore, a decline in polyamine biosynthesis gene expression in rat lateral and ventral prostate cells during cancer progression may enhance the availability with an inhibitory effect on former and stimulatory of SAM pool for epigenetic modification Massie( et al. effect on latter (Costello et al. 1995, 2000). Although 2017). The absence of the Warburg effect in early stage bio-energetically less efficient, the citrate production is PCa is clinically relevant as these tumours do not appear essential to maintain the pH of the semen, chelation of on fluorodeoxyglucose positron emission tomography calcium ions by citrate (Ford & Harrison 1984) and may (FDG-PET) scans (Liu et al. 2001). However, in the later have more complex roles. Furthermore, a relatively low stages, PCa cells start exhibiting Warburg effect, and abundance or absence of ATP citrate lyase (ACLY) by FDG-PET may be useful in monitoring treatment response negative regulation through miR-22 (Xin et al. 2016) may in advanced metastatic PCa (Eidelman et al. 2017). Early- be preventing the degradation of citrate to acetyl CoA and stage PCa appears to rely on lipids for energy production, OAA in the cytosol thereby promoting its secretion into and this property is exploited in visualising tumours the prostatic fluid. Interestingly, ACLY, a key enzyme in by 11C-acetate or 11C-choline accumulation, which the de novo lipogenesis has been shown to be upregulated seems to be a more sensitive imaging technique than in clinical samples from PCa, BCa osteosarcoma, cervical FDG-PET in the detection of primary and metastatic PCas cancer and lung cancer with a concomitant reduction in (Jadvar 2012). 11C-sarcosine is also gaining interest as a miRNA-22 (Xin et al. 2016). To summarise, normal prostate radiotracer for PCa imaging as sarcosine, a metabolic cells are characterised by a high net citrate production product of choline is associated with PCa aggressiveness associated with a low level of oxidative phosphorlyation and progression (Piert et al. 2017). In BCa, most studies (OXPHOS) and high rate of glycolysis. have focused on18F-labelled thymidine analogues to A metabolic transformation from a zinc-accumulating assess cell proliferation, although promising results from citrate-secreting cell to citrate-oxidising cell is a prominent using 11C-choline have been reported in BCa patients feature of prostate malignancy. Patient-derived tumour (Kenny 2016). metabolomics data demonstrate strikingly low citrate The metabolic characteristics of mammary epithelial levels in CRPC tumours when compared to normal cells change with tumour onset and metastatic disease prostate and in androgen-dependent PCa (Shafi et al. progression to sustain augmented biosynthetic demand. 2015). ZIP1 gene expression is markedly downregulated One metabolomic study in a syngeneic mouse mammary in adenocarcinomatous glands coupled with a loss of tumour model observed metabolite alterations in a number zinc accumulation (Franklin et al. 2005). Two other of pathways involved in glycolysis, the pentose phosphate zinc transporter isoforms ZIP2 and ZIP3 are also pathway and a decrease in GSH-dependent antioxidative downregulated in PCa (Desouki et al. 2007). Cancer cells pathway, and intermediates in lipid biosynthesis like tend to evade the inefficient process of citrate production fatty acid synthase (FASN) (Lu et al. 2010). Moreover, through epigenetic silencing of zinc transporters by metabolomic analysis of 270 BCa samples and 97 normal promoter hypermethylation thereby inhibiting zinc breast samples has highlighted a switch from a positive to

Figure 2 (A) Key metabolic differences between ER-positive and ER-negative breast tumours. (B) Schematic diagram showing role of glutamine and cholesterol metabolite, 27-OHC in supporting tumour growth. AI, aromatase inhibition; CYP27A1, cytochrome P450 family 27 subfamily A member 1; CYP7B1, cytochrome P450 family 7 subfamily B member 1; GLS, glutaminase; GLUD, glutamate dehydrogenase; SLC1A5, solute carrier family 1 member 5; SLC7A5, SLC family 7 member 5; 27-OHC, 27-hydroxyl cholesterol. negative correlation between glutamate and glutamine in and metabolic studies are corroborative of the role of AR tumour vs normal, indicating that BCa cells, particularly as a core regulator of an anabolic transcriptional network ER-negative tumours have a metabolic dependency on in PCa. Studies by Massie et al. have sought to derive a glutamine metabolism (Fig. 2) (Budczies et al. 2015). detailed map of AR-regulated genes in PCa cell lines Notably, c-MYC amplification is found in 15.7% of all representing distinct molecular subtype of the disease, by BCa s (Deming et al. 2000). In ER-positive breast tumours, employing ChIP seq and transcript profiling Massie( et al. it is known to confer response to endocrine treatment 2011). Stimulation of AR by androgen upregulated genes (Ellis et al. 2012) and implicated in the development of involved in cell cycle, glucose uptake and glycolysis, lipid treatment resistance (Venditti et al. 2002, McNeil et al. turnover, nucleotide and amino acid metabolism. This 2006, Miller et al. 2011). Similarly, in the absence of study identified calcium/calmodulin-dependent protein ER, one characteristic of triple-negative BCa (TNBC) is kinase 2 (CAMKK2) as a hormone-dependent modulator increased transcriptional activity of the c-MYC oncogene of anabolic metabolism in PCa in an AMP-activated (Alles et al. 2009). It is established that high expression protein kinase (AMPK)-dependent manner (Massie et al. of c-MYC can augment glutamine uptake and maintain 2011). CAMKK2 is also consistently overexpressed in the elevated bioenergetic demands of a tumourigenic cell clinical samples from both hormone sensitive and CRPC. (Anso et al. 2013). Interestingly, a recent study by Mishra AR-mediated activation of cellular fuel sensor, AMPK and et al. reported elevated levels of the oncometabolite D-2- downstream AMPK-PGC1α signalling axis confers distinct hydroxyglutarate in ER-negative breast tumours driven growth advantage to the tumour cells (Tennakoon et al. by the c-MYC-induced mitochondrial enzyme, alcohol 2014). Consequently, genetic changes in AR form one of dehydrogenase iron-containing protein 1, promoting the core contributors to altered cellular metabolism in metabolic reprogramming, reductive glutamine PCa. C-MYC is another TF overexpressed in PCa, which metabolism and disease progression (Mishra et al. 2018). partially overlaps with AR-binding sites and antagonises Akin to lipid metabolism in PCa, glutamine metabolism AR-mediated transcriptional output (Barfeld et al. 2017). requires mitochondrial function and oxidative However, in molecular apocrine BCa, MYC cooperates with phosphorylation. AR in androgen-responsive gene transcription contrary The role of sex hormones and nuclear hormone to the antagonistic relationship seen in PCa (Ni et al. receptors in the metabolic transformation of prostate or 2013). In vitro studies provide important insights into the breast is quite complex and inadequately understood, with intricate transcriptional and gene regulatory networks several caveats in existing information linking genetic and and target genes relevant to the progression of PCa and molecular changes to metabolic transformation. Genomic BCa. However, in order to get a comprehensive picture of

http://erc.endocrinology-journals.org © 2018 Society for Endocrinology https://doi.org/10.1530/ERC-18-0048 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 06:03:19AM via free access Endocrine-Related N Poulose et al. From hormones to fats and 25:9 R440 Cancer back the mechanisms underpinning the disease, it is important in monocarboxylate transporter (MCT4) expression and to simultaneously derive and interpret data from in vivo lactate dehydrogenase activity (LDH) (Vaz et al. 2012). models, tissue explants and clinical specimens. GLUTs and MCTs may be functioning synchronously to maintain glycolysis at a steady rate in solid tumours. However, in PCa, a reciprocal metabolic relationship seems Metabolic pathways in prostate and breast to exist between cancer-associated fibroblast (CAFs) and cancers cancer cells. When co-cultured, CAFs undergo metabolic reprogramming to a Warburg phenotype with increased Metabolite transporters GLUT1, lactate production and efflux through MCT4, An increase in glucose uptake and switching to aerobic whereas PCa cells are shifted to aerobic metabolism with glycolysis or Warburg effect is a prominent metabolic an increase in lactate upload via MCT1. The allocation alteration in most cancers. However, the prostate has of glycolytic metabolism to CAFs and ‘lactate shuttling’ a unique metabolic landscape that favours switching appears to be one of the strategies employed by PCa cells to an increased OXPHOS during cancer initiation and for growth and progression (Fiaschi et al. 2012). MCT2 is progression. Glucose uptake and increased glycolysis yet another MCT isoform overexpressed in PCa through appears to be a metabolic adaptation in the late stage epigenetic regulation (Pertega-Gomes et al. 2015b). These of the disease correlated with poor prognosis (Pertega- studies indicate that MCTs could be promising targets in Gomes et al. 2015a). Studies from our group and others the treatment of PCa. have shown androgen-stimulated glucose uptake and lactate production in PCa cell lines (Massie et al. 2011, Amino acid metabolism Vaz et al. 2012). The expression of ubiquitous glucose transporter, GLUT1, was elevated by androgen treatment Many cancers show increased dependency on glutamine in these cells. A recent study has further validated the uptake and metabolism, which not only serves the critical role played by GLUT1 in PCa, the knockdown of protein synthesis requirements but also fuels TCA cycle which inhibited glycolysis, cell proliferation and induced (anaplerosis) and acts a source of fatty acid production cycle arrest at G2/M phase (Xiao et al. 2018). Other GLUT through reductive carboxylation (Mullen et al. 2011, isoforms like GLUT3 (Vaz et al. 2012), insulin-sensitive Eidelman et al. 2017). Glutaminolysis involves conversion isoforms GLUT4, GLUT12 (Chandler et al. 2003) and of glutamine to glutamate by glutaminase, which is then fructose transporter GLUT5 (Reinicke et al. 2012) are also transformed into alpha-ketoglutarate that is fed into the reported in PCa cells. Similarly, GLUT1, GLUT2, GLUT3, Krebs cycle. Glutaminase 1 expression is augmented in GLUT4, GLUT5 and GLUT12 have been reported to be PCa patients and is highly correlated with the stage of expressed in BCa cells (Rogers et al. 2003, Godoy et al. the disease (Pan et al. 2015). The expression of major 2006, Garrido et al. 2013). GLUT1 expression has been glutamine transporter in cancer cells, alanine–serine– shown to positively correlate with ERα positivity and cysteine transporter‐2 (ASCT2), is also elevated in PCa confer a more aggressive disease and poorer prognosis patient samples (Wang et al. 2015). Indeed, inhibition in BCa patient tumour samples (Kang et al. 2002). of ASCT2 limited PCa growth and metastasis in vivo and Downregulation of GLUT1 with the multi-kinase hence a putative therapeutic target. inhibitor sorafenib has been shown to induce apoptosis Among the other metabolic pathways, MYC-regulated through mitochondrial membrane depolarisation and purine biosynthesis has been shown to be significant AMPK-dependent inhibition of the mTORC1 pathway in in PCa with two reported biomarkers in the pathway BCa (Fumarola et al. 2013). Further studies are needed to namely, phosphoribosylaminoimidazole carboxylase and delineate the specific roles of these GLUT isoforms in PCa phosphoribosylaminoimidazole-succinocarboxamide and BCa. synthase and inosine monophosphate dehydrogenase Monocarboxylate transporters (MCTs) are proton 2 (IMPDH2); inhibition of IMPDH2 impaired cell symporters involved in lactate efflux to maintain the high proliferation in vitro by inducing nucleolar stress glycolytic rate seen in solid tumours and to prevent the (Barfeld et al. 2015). Recent studies have shown that cytotoxicity from acidosis (Pinheiro et al. 2012). Androgen- enzymes in the hexosamine biosynthetic pathway responsive (LNCaP) and androgen-nonresponsive (PC3) are androgen regulated and upregulated in PCa cell lines exhibited distinct glycolytic profiles with a higher transcriptionally and metabolically. The enzyme involved lactate production in PC3 and a concomitant increase in O-linked conjugation, O-linked β-N-acetylglucosamine

Figure 3 Schematic diagram showing SREBP-mediated lipogenic programme and pathways involved in lipid and cholesterol biosynthesis. The pathways are shown in blue arrows, key metabolic enzymes upregulated in PCa and BCa in blue boxes, inhibitors of the enzymes are in red.

http://erc.endocrinology-journals.org © 2018 Society for Endocrinology https://doi.org/10.1530/ERC-18-0048 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 06:03:19AM via free access Endocrine-Related N Poulose et al. From hormones to fats and 25:9 R442 Cancer back the lipogenic switch in PCa cells. One of the mechanisms programme in a MAPK-dependent manner and can be by which androgens exert this lipogenic switch is through blocked by SREBP inhibitor, fatostatin. Intriguingly, a activation of sterol regulatory element-binding proteins high-fat diet was sufficient to drive metastasis in PTEN-null (SREBPs), master regulators of lipid and cholesterol model highlighting the importance of dietary intervention biosynthesis. SREBP family of TFs encompasses SREBP-1a, in regulating PCa progression (Chen et al. 2018a). SREBP SREBP-1c and SREBP-2, which share similar structure and pathways are also activated by mutant p53, often seen in mechanism of activation. In brief, SREBP precursors are metastatic PCa. In fact, fatostatin alone or in combination anchored to endoplasmic reticulum membrane where it with docetaxel displayed significant antitumor effects forms a complex with SREBP cleavage-activating protein in PCa xenograft models (Li et al. 2015). Studies in an (SCAP), which in turn interacts with a retention protein LNCaP xenograft model of human PCa indicate increased complex. The loss of interaction between SCAP and lipogenesis as an adaptive mechanism during progression retention complex leads to the migration of SREBP/SCAP to androgen independence (Ettinger et al. 2004). These complex to the golgi where it is subjected to proteolytic studies significantly enhance our understanding of the cleavage by resident proteases and subsequent release of mechanistic basis for dysregulated lipid metabolism in N-terminal SREBP segment. NSREBP further translocates PCa and could open doors to new approaches for patient to the nucleus and binds to SREs in the promoter region stratification and molecular subtyping. of key lipogenic genes involved in both the synthesis of FASN, an AR target gene and a key enzyme in the fatty acids and cholesterol (Heemers et al. 2006). SREBP- lipid biosynthetic pathway, is frequently upregulated in dependent de novo lipogenesis promotes PCa growth and human PCa and BCa and has been widely studied. The metastases. Huang et al. has shown a positive correlation recent development of Fasnall, a FASN inhibitor with between SREBP1 protein expression and clinical anti-tumour activity (Alwarawrah et al. 2016), provides an Gleason score in PCa (Huang et al. 2012). Androgen- interesting therapeutic opportunity. FASN expression is induced SREBP activation is proposed to occur through an early event in the development of PCa with a gradual increased AR-induced expression of SCAP, which favours increase with the stage of cancer and a higher expression SREBP/SCAP translocation to the golgi and activation correlates with poor prognosis and patient survival, (Heemers et al. 2006). SREBP1 in turn regulates the suggesting the use of FASN as a general PCa marker expression of AR by binding to its promoter region (Huang (Swinnen et al. 2002, Rossi et al. 2003). It is noteworthy et al. 2012) thereby maintaining the lipogenic phenotype. that many of the oncogenic signalling pathways are Two recent studies have identified novel genomic involved in the regulation of lipid metabolism. Growth drivers of lipid metabolism in PCa with implications factor-associated signalling pathways like PI3K/Akt and for subtyping and treatment of the disease. Both studies MAPK regulates FASN expression through SREBP1 (Zhang employed PTEN-null transgenic mouse model of PCa, & Du 2012). Other TFs such as Sp1, members of p53 which gives high-grade intraepithelial prostate tumours family and the lipogenesis-related nuclear protein S14 at an early age and invasive PCa at a late stage. The first are also known to modulate FASN expression (Zhang & study focused on PDH complex (PDC), a complex with Du 2012). FASN is also regulated post-translationally in a gatekeeper function in converting pyruvate into acetyl PCa by androgen-regulated ubiquitin-specific protease-2a CoA for entry into the TCA cycle in mitochondria, (USP2a) that removes ubiquitin residues from FASN and demonstrates how cellular metabolism is intimately linked stabilises the protein. USP2a is overexpressed in PCa and to the regulation of gene expression. By inactivating represents another therapeutic target (Graner et al. 2004). pyruvate dehydrogenase A1 (PDHA1), prostate tumour Other enzymes involved in fatty acid synthesis, which growth was restrained at an early stage mainly through are frequently upregulated in PCa are ACLY (Xin et al. suppressing lipid biosynthesis. Mechanistically, this is 2016), acetyl CoA carboxylase (ACC) that catalyses the due to reduced histone acetylation at regulatory regions conversion of acetyl CoA to malonyl CoA and stearoyl- bound by SREBP owing to a reduction in the activity CoA desaturases (SCDs), rate-limiting enzyme in the nuclear compartmentalised PDHA1 (Chen et al. 2018b). biosynthesis of monounsaturated fatty acids (Kim et al. Furthermore, PDHA1 is frequently amplified and 2011). It is interesting to note that SCD peptides derived overexpressed in these tumours signifying its potential as from proteolytic cleavage of SCD can transactivate AR and a therapeutic target. The second study utilises the same facilitate cell proliferation (Kim et al. 2011). genetic background and found that co-deletion of Pml SREBP-1 has additionally been shown to confer poor leads to hyperactivation of an SREBP dependent lipogenic clinical prognosis in BCa and promote invasive and

Figure 4 Steroid hormone biosynthesis pathway. A schematic representation highlighting the structural similarities of cholesterol, testosterone, oestradiol and DHEA in the biosynthesis of cholesterol-derived steroid hormones and the key enzymes involved. CYP11A1, cytochrome P450 family 11 subfamily A; CYP17A1, cytochrome P450 family 17α-hydroxylase/17,20-lyase; 3β-HSD, 3β-hydroxysteroid dehydrogenase.

http://erc.endocrinology-journals.org © 2018 Society for Endocrinology https://doi.org/10.1530/ERC-18-0048 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 06:03:19AM via free access Endocrine-Related N Poulose et al. From hormones to fats and 25:9 R444 Cancer back acetate, an inhibitor of 17α-hydroxylase and C17,20 Treatment resistance in AR-positive and lyase (CYP17A1) for the treatment of men with advanced ER-positive cancers CRPC (Ryan et al. 2013). In fact, genetic polymorphisms of CYP17A1 are associated with higher aggressiveness AR plays a central role in the pathogenesis of PCa and and risk of progression to CRPC in patients receiving is the main therapeutic target. Several studies indicate androgen deprivation therapy (Robles-Fernandez et al. that polymorphisms/mutations in the AR predispose men 2017). The importance of cholesterol in PCa progression to PCa (Gottlieb et al. 2012). For instance, polymorphic is further established by a clinical study by Platz et al. variation in the length of CAG repeats in the amino where the use of statins (cholesterol-lowering drugs) terminus of AR is found to be inversely correlated to AR in patients is found to be associated with reduced risk transcriptional activity, with short repeats associated of metastatic PCa (Platz et al. 2006). The cholesterol with an increased risk of PCa (Heinlein & Chang 2004). metabolite, 27-hydroxyl-cholesterol (27-OHC) is a known Although disputed, this association may partly explain the selective ER modulator, which promotes tumourigenesis ethnic differences seen in PCa incidence, where African- in ER-positive BCa (Fig. 2) (Warner & Gustafsson 2014). American men have short CAG repeat length and higher Higher levels of 27-OHC have been reported in ERα- incidence, and the vice versa with Asian men (Heinlein positive breast tumours in comparison to normal breast & Chang 2004). The initiation of PCa may involve gene tissue, along with an observed reduction in the 27-OHC- rearrangements that activate common growth-promoting metabolising enzyme CYP7B1 (Wu et al. 2013). In vivo pathways (Tomlins et al. 2005, Hermans et al. 2006). xenograft experiments have additionally shown that Dysregulation of PI3K/Akt and RAS/RAF pathways are 27-OHC alone is sufficient to support oestrogenic activity also implicated in PCa initiation and progression. Early- in ER-dependent BCa models, providing rationale for stage PCa can be treated by castration through surgical 27-OHC targeting (Wu et al. 2013). Similar to the Chen (orchiectomy) or chemical means. Chemical castration et al. study in PCa, a high-cholesterol diet alone increased involves use of gonadotropin-releasing hormone (GnRH) the growth and metastasis of ER-positive tumours in a analogues such as leuprolide and goserelin or GnRH mouse BCa model (Nelson et al. 2013). antagonist such as degarelix. Patients are also subjected Obesity is major challenge faced by the modern to androgen deprivation therapy (ADT) by treatment society and associated with pathogenesis of cardiovascular with anti-androgens, which are AR ligands that compete diseases and type 2 diabetes. Obesity is also a driving force for AR-binding sites. The steroidal anti-androgens are in incidence and increased recurrence of PCa and BCa. now replaced with non-steroidal ones such as flutamide, Besides de novo adipogenesis induced in these cancers, bicalutamide and nilutamide (Tan et al. 2015). The adipocyte-derived fatty acids also accelerate cancer second-generation AR antagonist enzalutamide is a progression. Although the tumour microenvironment of more potent antagonist with higher affinity than the PCa and BCa differ, emerging evidence suggests a similar first-generation counterparts. Abiraterone acetate that relationship between local adipocytes and PCa and BCa blocks androgen biosynthesis is clinically approved and cells. The lipid content of peri-prostatic and mammary used in combination with prednisone as a treatment for adipocytes is proportionately increased during obesity. metastatic CRPC (Auchus et al. 2014). An in vitro co-culture of obese adipocytes with breast Although ADT or chemical castration remains first or PCa cell lines, showed a higher rate of transfer of line of treatment of PCa, disease eventually progresses to FA from adipocytes to the cancer cells correlated with castration-resistant mode, which is ultimately fatal. AR is increased proliferation and survival (Balaban et al. 2017). expressed throughout cancer progression and remains a Interestingly, it is the peripheral zone of the prostate, major driving force for CRPC. Clinical and experimental which is more susceptible to becoming cancerous and evidence suggests a positive correlation between AR is enriched in genes regulating lipid metabolism like expression and lower recurrence-free survival and disease FASN, ACACA, ACSL1 and ACSL3. Together, these studies progression. Different mechanisms have been proposed underscore the importance of targeting intermediates to explain the progression to CRPC like (1) AR gene in the lipid/cholesterol biosynthetic pathway in the amplifications enabling increased sensitivity of the AR treatment of PCa. De novo lipid biosynthesis requires the to its agonists under conditions of androgen deprivation; substrates acetyl CoA and NADPH. Therefore, lipogenesis (2) overexpression of AR coregulators such as SRC1, SRC-3, is coupled to other metabolic pathways like glucose and CDC25B, TIP60 and NMT55, allowing AR sensitisation at glutamine to derive these substrates (Zhang & Du 2012). low levels of androgens; (3) AR mutations that render the

http://erc.endocrinology-journals.org © 2018 Society for Endocrinology https://doi.org/10.1530/ERC-18-0048 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 06:03:19AM via free access Endocrine-Related N Poulose et al. From hormones to fats and 25:9 R445 Cancer back receptor responsive to alternate, non-androgen ligands like endocrine therapy resistance. Consequently, a number oestrogen, progesterone, cortisol and anti-androgens; (4) of clinical trials combining such therapies with those ligand-independent AR activation such as that mediated that target HER2 such as gefitinib have been undertaken, by IL6, the circulating levels of which is often higher in yet unpublished to date (Baselga et al. 2005; https:// metastatic PCa (Hobisch et al. 1998); (5) interaction with clinicaltrials.gov/ct2/show/NCT00080743; https:// tumour suppressors like PTEN, the loss of which in PCa clinicaltrials.gov/ct2/show/NCT00632723). The growth may increase AR turnover and hence transcriptional factors and signalling pathways driven by these tumours, activity and (6) AR-independent mechanisms (Heinlein despite their growth factor dependency switch, regulate & Chang 2004, Tan et al. 2015). The acquisition of some BCa tumour metabolism. AR mutations that renders AR transcriptional activity by Alterations in both tumour epigenomic and allowing anti-androgens like bicalutamide (Hara et al. transcriptomic profiles post endocrine treatment have 2003) and adrenal androgens DHEA and androstenediol been observed in vitro and in vivo by the Magnani to function as transcriptional agonists is a frequent group following the generation of endocrine therapy cause of failure of ADT. Consequently, antiandrogen resistance BCa cell lines and NOD-SCID mouse metastatic withdrawal syndrome is observed in a proportion of model generation (Nguyen et al. 2015). The epigenetic patients with failure of ADT, with tumour regression reprogramming of ERα-positive BCas, in particular after discontinuation of antiandrogen treatment. For a H3K27ac modifications in promoter-proximal regions detailed description of various mechanisms leading to has been shown to occur and potentiate endocrine failure of ADT, audience is directed to reviews by Heinlein therapy resistance mechanisms following treatment & Chang (Heinlein & Chang 2004) and Karantanos et al. and particularly augment metastatic development. A (Karantanos et al. 2013). number of H3K27ac alterations in close proximity to the In BCa, endocrine therapies such as tamoxifen, promoters of several genes, which are already known to be aromatase inhibitors (AIs), including letrozole and involved in endocrine therapy resistance were observed anastrozole and the ER antagonists Faslodex (fulvestrant) (Magnani et al. 2013). In addition, the upregulation of target circulating oestrogen and consequently, deprive the cholesterol biosynthesis (CB) pathway in AI-resistant ER-dependent tumour cells of ligand activation. However, BCa cells was also reported, including the upregulation both intrinsic and acquired de novo resistance to endocrine of a number of genes, which are known to regulate the therapies occurs in a subset of patients. Breast tumour synthesis of 27-OHC (Nguyen et al. 2015). It is known that resistance to ER-targeted therapies has clinically been 27-OHC facilitates the oestrogen-independent binding of observed to occur via a plethora of mechanisms, with ERα to a plethora of genomic regulatory loci and hence such tumours, reverting to low expression of ERα and can drive ER-dependent transcription when endogenous thus losing their ER-driven phenotype (Osborne & Schiff levels of oestrogen are low following endocrine therapy 2011). ER-positive BCas have clinically been shown to (Nelson et al. 2013). Furthermore, endocrine therapy revert to a HER2-driven dependency following endocrine can directly regulate cellular cholesterol metabolism by treatment, predominately, via HER2 gene amplification or targeting the cholesterol epoxide hydrolase enzymatic overexpression (Meng et al. 2004, Gutierrez et al. 2005, complex and the generation of the oncometabolite Lipton et al. 2005). Several pre-clinical studies have oxysterol 6-oxo-cholestan-3β,5α-diol, otherwise referred highlighted that breast tumours can alternate between an to as OCDO (Leignadier et al. 2017, Voisin et al. 2017). ER and HER2 dependency following prolonged targeted OCDO drives BCa progression by facilitating the nuclear therapy exposure (Meng et al. 2004, Gutierrez et al. 2005, translocation of the glucocorticoid receptor (GR) and Lipton et al. 2005, Massarweh et al. 2008). Growth factor consequently, leads to the transcriptional activation receptor overexpression is one method by which tumours of a number of GR target genes involved in endocrine can circumvent endocrine therapy responsiveness, in therapy resistance (Voisin et al. 2017). The Magnani addition to HER2, IGF, FGF, VEGF and Src have also been group has developed a CB signature that could be used identified as ER-independent drivers of ER-positive BCa in ERα-positive BCa patients to stratify before adjuvant in response to hormone-targeted therapy (Arpino et al. treatment, to determine whether they are likely to 2008, Morgan et al. 2009, Chakraborty et al. 2010). Similar develop endocrine therapy tumour resistance via the to HER2, the pathways regulated by such receptors and upregulation of the CB pathway and potentially benefit their corresponding ligands are frequently overexpressed from adjuvant metabolic inhibitor treatment (Nguyen or genetically amplified in a number of clinical cases of et al. 2015).

Table 1 Metabolic inhibitors in pre-clinical and clinical studies.

Clinical trial Drug Pathway target Mechanism of action status Source Metformin Energy production AMPK activator inhibits Ongoing Chen et al. (2018a), Chae pathways mitochondrial complex I, lipid and clinical trials et al. (2016), NCT01980823 protein synthesis and glycolysis (www.clinicaltrials.gov) Sorafenib Lipid metabolism Multi-kinase inhibitor Phase III Zhu et al. (2015) clinical trials Fatostatin Lipogenesis SREBP1 and SREBP2 inhibitor Pre-clinical Guo et al. (2014), Li et al. (2014) Fasnall, TVB-2640, Fatty acid synthesis FASN inhibitors Ongoing NCT03179904 (www. Carulenin, C75, clinical trials clinicaltrials.gov) Orlistat BMS 303141, SB Glycolysis and lipid ATP citrate lyase (ACLY) inhibitors Pre-clinical Hatzivassiliou et al. (2005), 204990 synthesis Zhao et al. (2016) Phloretin Glucose transport GLUT1 and GLUT4 Pre-clinical Ma et al. (2016), Min et al. (2015), Wu et al. (2009) 3-bromopyruvate Glycolysis Hexokinase inhibition and inhibition Pre-clinical Ho et al. (2016) of other glycolytic enzymes Statins; atorvastatin Cholesterol/lipid HMG-CoA synthase (HMGCS) Clinical trials Chen et al. (2018a) metabolism inhibitors SCD1 inhibitor Lipid metabolism Stearoyl-CoA desaturase 1 (SCD1) Pre-clinical Chen et al. (2016), Mason inhibitor et al. (2012) ACC inhibitor; Fatty acid synthesis Acetyl CoA carboxylase (ACC) Phase III Chen et al. (2018b), Griffith ND-630, GS-0976 inhibitor clinical trials et al. (2014), NCT02781584 (www.clinicaltrials.gov) CYP17A1 inhibitors; Steroid hormone Cytochrome P450 Phase III NCT00268476, NCT01842321 abiraterone metabolism 17α-hydroxylase/17,20-lyase clinical trials (www.clinicaltrials.gov) (CYP17A1) inhibitors

Conclusion and future directions: biochemical measures such as insulin, IGF, leptin and stratification of prostate and breast cancer adipokine concentrations, assessment of obesity and BMI of the patient along with etiologic heterogeneity. The use of Studies have highlighted the importance of studying metabolic inhibitors would warrant a careful examination metabolic characteristics of PCa and BCa in order to of patient metabolic history as these cancers are influenced subtype the diseases and accelerate the discovery of novel by metabolic disorders. Therefore, it is important to metabolic biomarkers in the diagnosis of these cancers. consider the medical history of patients, existing drugs used PSA is a widely used biomarker in PCa but is also elevated like metformin and statins and the presented side effects. in men with benign prostatic hyperplasia and prostatitis, Thus, the successful clinical application of metabolic drugs which limits its usefulness (Nicholson & Ricke 2011). A lies in clinical trial patient stratification and combination combinatorial approach involving transcriptomic, ChIP, therapy with existing drugs. proteomic and metabolomic data are currently employed to study novel biomarkers for early detection of these cancers. Novel approaches to quantify lipids like vibrational Raman Declaration of interest microspectroscopy are being developed, which could be The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review. a sensitive technique for tumour diagnosis and staging (O’Malley et al. 2017). Further stratification incorporating metabolite and lipogenic gene markers might prove Funding beneficial in the accurate diagnosis and treatment of the The article does not present primary research; however, the authors disease. The overexpression of SREBP and FASN in PCa would like to acknowledge the support of Prostate Cancer UK/Movember (R E S and I G M), the Norwegian Research Council (N P) and the John Black and BCa makes them attractive therapeutic targets. Other Foundation (I G M). potential therapeutic targets include ACLY, PDH, ACC and SCD. A more detailed understanding of dysregulated lipid metabolism will help in designing better drugs or Author contributions statement N P and R E S wrote the text and made the figures and table. I G M repurposing those that are already developed (Table 1). conceived the structure of the review and contributed to the writing of It would also be beneficial to incorporate a spectrum of the text.

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Received in final form 10 May 2018 Accepted 14 May 2018 Accepted Preprint published online 14 May 2018