Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/105539
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Type: Journal article
Title: Androgen and estrogen receptors in breast cancer coregulate human UDP-glucuronosyltransferases 2B15 and 2B17
Author: Hu, D.
Selth, L.
Tarulli, G.
Meech, R.
Wijayakumara, D.
Chanawong, A.
Russell, R.
Caldas, C.
Robinson, J.
Carroll, J.
Tilley, W.
Mackenzie, P.
Hickey, T.
Citation: Cancer Research, 2016; 76(19):5881-5893
Publisher: American Association for Cancer Research
Issue Date: 2016
ISSN: 0008-5472
1538-7445
Statement of
Responsibility: 
Dong 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
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.
Keywords: Cell Line, Tumor; Humans; Breast Neoplasms; Anilides; Glucuronosyltransferase; Receptor, erbB-2; Receptors, Androgen; Estrogen Receptor alpha; Minor Histocompatibility Antigens; Female; Hepatocyte Nuclear Factor 3-alpha; Promoter Regions, Genetic
Rights: ©2016 AACR
RMID: 0030053797
DOI: 10.1158/0008-5472.CAN-15-3372
Grant ID: http://purl.org/au-research/grants/nhmrc/1008349
http://purl.org/au-research/grants/nhmrc/1084416
Appears in Collections:Medical Education Unit publications

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