Androgen and Estrogen Receptors in Breast Cancer Coregulate Human UDP-Glucuronosyltransferases 2B15 and 2B17.

Dong G Hu,Luke A Selth,Carlos Caldas,Roslin Russell,Peter I Mackenzie,Theresa E Hickey,Jason S Carroll,Jessica L.L Robinson,Dhilushi Wijayakumara,Wayne D Tilley,Apichaya Chanawong,Gerard A Tarulli,Robyn Meech

doi:10.1158/0008-5472.can-15-3372

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.

Highlights

Breast and prostate cancer are the most common forms of hormone-dependent cancer and account for a major proportion of cancer-related deaths in women and men, respectively
In the METABRIC cohort, ERaþ cases had significantly higher expression of these genes compared to ERaÀ cases (Fig. 1B), and highest expression was observed in integrative cluster 1, predominantly composed of ERaþ, luminal B breast cancers (Fig. 1C)
Higher levels of UGT2B17 were significantly associated with increased survival outcomes in cases classified into iCluster 5, largely composed of high-grade breast cancers with HER2 amplification and very poor survival outcomes, as well as all cases in the cohort classified as being HER2 amplified by SNP6 array analysis (Fig. 1E)

Summary

Introduction

Breast and prostate cancer are the most common forms of hormone-dependent cancer and account for a major proportion of cancer-related deaths in women and men, respectively. Breast cancer is predominantly driven by aberrant estrogen receptor alpha (ERa) signaling and prostate cancer by aberrant androgen receptor (AR) signaling. These diseases display multiple similarities of etiology and pathology [1]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). D.G. Hu and L.A. Selth contributed to this article

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