Androgen and estrogen receptors in breast cancer coregulate human UDP-glucuronosyltransferases 2B15 and 2B17

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dc.contributor.authorHu, D.
dc.contributor.authorSelth, L.
dc.contributor.authorTarulli, G.
dc.contributor.authorMeech, R.
dc.contributor.authorWijayakumara, D.
dc.contributor.authorChanawong, A.
dc.contributor.authorRussell, R.
dc.contributor.authorCaldas, C.
dc.contributor.authorRobinson, J.
dc.contributor.authorCarroll, J.
dc.contributor.authorTilley, W.
dc.contributor.authorMackenzie, P.
dc.contributor.authorHickey, T.
dc.date.issued2016
dc.description.abstractGlucuronidation 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.
dc.description.statementofresponsibilityDong G. Hu, Luke A. Selth, Gerard A. Tarulli, Robyn Meech, Dhilushi Wijayakumara, Apichaya Chanawong, Roslin Russell, Carlos Caldas, Jessica L.L. Robinson, Jason S. Carroll, Wayne D. Tilley, Peter I. Mackenzie and Theresa E. Hickey
dc.identifier.citationCancer Research, 2016; 76(19):5881-5893
dc.identifier.doi10.1158/0008-5472.CAN-15-3372
dc.identifier.issn0008-5472
dc.identifier.issn1538-7445
dc.identifier.orcidSelth, L. [0000-0002-4686-1418]
dc.identifier.orcidTilley, W. [0000-0003-1893-2626]
dc.identifier.orcidHickey, T. [0000-0002-2752-730X]
dc.identifier.urihttp://hdl.handle.net/2440/105539
dc.language.isoen
dc.publisherAmerican Association for Cancer Research
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1008349
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1084416
dc.rights©2016 AACR
dc.source.urihttps://doi.org/10.1158/0008-5472.can-15-3372
dc.subjectCell Line, Tumor
dc.subjectHumans
dc.subjectBreast Neoplasms
dc.subjectAnilides
dc.subjectGlucuronosyltransferase
dc.subjectReceptor, erbB-2
dc.subjectReceptors, Androgen
dc.subjectEstrogen Receptor alpha
dc.subjectMinor Histocompatibility Antigens
dc.subjectFemale
dc.subjectHepatocyte Nuclear Factor 3-alpha
dc.subjectPromoter Regions, Genetic
dc.titleAndrogen and estrogen receptors in breast cancer coregulate human UDP-glucuronosyltransferases 2B15 and 2B17
dc.typeJournal article
pubs.publication-statusPublished

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