title: Androgen and Estrogen Receptors in Breast Cancer Coregulate Human UDP-Glucuronosyltransferases 2B15 and 2B17.
abstract: Glucuronidation is an enzymatic process that terminally inactivates steroid hormones, including estrogens and androgens, thereby influencing carcinogenesis in hormone-dependent cancers. While estrogens drive breast carcinogenesis via the estrogen receptor alpha (ERα), androgens play a critical role as prohormones for estrogen biosynthesis and ligands for the androgen receptor (AR). In this study, the expression and regulation of two androgen-inactivating enzymes, the UDP-glucuronosyltransferases UGT2B15 and UGT2B17, was assessed in breast cancer. In large clinical cohorts, high UGT2B15 and UGT2B17 levels positively influenced disease-specific survival in distinct molecular subgroups. Expression of these genes was highest in cases positive for ERα. In cell line models, ERα, AR, and the transcription factor FOXA1 cooperated to increase transcription via tandem binding events at their proximal promoters. ERα activity was dependent on FOXA1, facilitated by AR activation, and potently stimulated by estradiol as well as estrogenic metabolites of 5α-dihydrotestosterone. AR activity was mediated via binding to an estrogen receptor half-site 3' to the FOXA1 and ERα-binding sites. Although AR and FOXA1 bound the UGT promoters in AR-positive/ERα-negative breast cancer cell lines, androgen treatment did not influence basal transcription levels. Ex vivo culture of human breast tissue and ERα+tumors provided evidence for upregulation of UGT2B15 and UGT2B17 by estrogen or androgen treatment. ERα binding was evident at the promoters of these genes in a small cohort of primary tumors and distant metastases. Collectively, these data provide insight into sex steroid receptor-mediated regulation of androgen-inactivating enzymes in ERα+breast cancer, which may have subtype-specific consequences for disease progression and outcomes. Cancer Res; 76(19); 5881-93. ©2016 AACR.
authors: Department of Clinical Pharmacology, Flinders University School of Medicine, Flinders Medical Centre, South Australia, Australia.
authors: Dong G
authors: DG
authors: Hu
authors: Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, The University of Adelaide, South Australia, Australia. Freemasons Foundation Centre for Men's Health, School of Medicine, The University of Adelaide, South Australia, Australia.
authors: Luke A
authors: LA
authors: Selth
authors: Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, The University of Adelaide, South Australia, Australia.
authors: Gerard A
authors: GA
authors: Tarulli
authors: Department of Clinical Pharmacology, Flinders University School of Medicine, Flinders Medical Centre, South Australia, Australia.
authors: Robyn
authors: R
authors: Meech
authors: Department of Clinical Pharmacology, Flinders University School of Medicine, Flinders Medical Centre, South Australia, Australia.
authors: Dhilushi
authors: D
authors: Wijayakumara
authors: Department of Clinical Pharmacology, Flinders University School of Medicine, Flinders Medical Centre, South Australia, Australia.
authors: Apichaya
authors: A
authors: Chanawong
authors: Breast Cancer Genomics Group, Cancer Research UK, Cambridge Institute, Cambridge University, Cambridge, United Kingdom.
authors: Roslin
authors: R
authors: Russell
authors: Breast Cancer Genomics Group, Cancer Research UK, Cambridge Institute, Cambridge University, Cambridge, United Kingdom.
authors: Carlos
authors: C
authors: Caldas
authors: Nuclear Transcription Factor Laboratory, Cancer Research UK, Cambridge Institute, Cambridge University, Cambridge, United Kingdom.
authors: Jessica L L
authors: JL
authors: Robinson
authors: Nuclear Transcription Factor Laboratory, Cancer Research UK, Cambridge Institute, Cambridge University, Cambridge, United Kingdom.
authors: Jason S
authors: JS
authors: Carroll
authors: Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, The University of Adelaide, South Australia, Australia. Freemasons Foundation Centre for Men's Health, School of Medicine, The University of Adelaide, South Australia, Australia.
authors: Wayne D
authors: WD
authors: Tilley
authors: Department of Clinical Pharmacology, Flinders University School of Medicine, Flinders Medical Centre, South Australia, Australia.
authors: Peter I
authors: PI
authors: Mackenzie
authors: Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, The University of Adelaide, South Australia, Australia. theresa.hickey@adelaide.edu.au.
authors: Theresa E
authors: TE
authors: Hickey
mesh_terms: D000813:Anilides / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000032:analysis*; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics / Q000502:physiology*; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000502:physiology; D006801:Humans; D015778:Minor Histocompatibility Antigens / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011944:Receptors, Androgen / Q000032:analysis*
chemical_list: D000813:Anilides; D047628:Estrogen Receptor alpha; D014453:Glucuronosyltransferase; D051541:Hepatocyte Nuclear Factor 3-alpha; D015778:Minor Histocompatibility Antigens; D018719:Erb-b2 Receptor Tyrosine Kinases; D011944:Receptors, Androgen; C410798:AR protein, human; C506487:ESR1 protein, human; C496499:FOXA1 protein, human; C472000:UDP-glucuronosyltransferase 2B15, human; C500513:UGT2B17 protein, human; C508053:ERBB2 protein, human; C547106:ostarine