25 9 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 f androgen studied in hormone-dependent cancers, and in particular, in prostate and breast cancer. f androgen receptor These cancers have strong similarities in the function of important transcriptional f breast drivers, such as the oestrogen and androgen receptors, at the level of dietary risk and f oestrogen epidemiology, genetics and therapeutically. In this review, we will focus on the function f 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 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 -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 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 R437 Cancer back in mitochondrial biogenesis, the TCA cycle and lipid Metabolic reprogramming in prostate and metabolism (Huss et al. 2004, Manavathi et al. 2013). breast cancer Consequently, the overexpression of ER-α, as observed in many Luminal A BCa tumours, leads to hormone- Understanding the unique metabolic landscape of normal dependent breast tumourigenesis (Barnes et