Downregulation of 15-hydroxyprostaglandin dehydrogenase during acquired tamoxifen resistance and association with poor prognosis in ERα-positive breast cancer.

Milene Volpato,Ping Fan,Philipp Y Maximov,Valerie Speirs,Abeer M Shaaban,Mark A Hull,Michele Cummings,V Craig Jordan,Reiner Hoppe,Balkees Abderrahman,Hiltrud Brauch,Bradley M Broom

doi:10.37349/etat.2020.00021

Abstract

Aim:Tamoxifen (TAM) resistance remains a clinical issue in breast cancer. The authors previously reported that 15-hydroxyprostaglandin dehydrogenase (HPGD) was significantly downregulated in tamoxifen-resistant (TAMr) breast cancer cell lines. Here, the authors investigated the relationship between HPGD expression, TAM resistance and prediction of outcome in breast cancer.Methods:HPGD overexpression and silencing studies were performed in isogenic TAMr and parental human breast cancer cell lines to establish the impact of HPGD expression on TAM resistance. HPGD expression and clinical outcome relationships were explored using immunohistochemistry and in silico analysis.Results:Restoration of HPGD expression and activity sensitised TAMr MCF-7 cells to TAM and 17β-oestradiol, whilst HPGD silencing in parental MCF-7 cells reduced TAM sensitivity. TAMr cells released more prostaglandin E2 (PGE2) than controls, which was reduced in TAMr cells stably transfected with HPGD. Exogenous PGE2 signalled through the EP4 receptor to reduce breast cancer cell sensitivity to TAM. Decreased HPGD expression was associated with decreased overall survival in ERα-positive breast cancer patients.Conclusions:HPGD downregulation in breast cancer is associated with reduced response to TAM therapy via PGE2-EP4 signalling and decreases patient survival. The data offer a potential target to develop combination therapies that may overcome acquired tamoxifen resistance.

Highlights

Due to its ability to bind to and modulate oestrogen receptor alpha (ERα) activity, Tamoxifen (TAM) was the first targeted therapy for breast cancer [1], with its widespread use in the clinic extending to four decades
Restoration of hydroxyprostaglandin dehydrogenase (HPGD) expression and activity sensitised TAMr MCF-7 cells to TAM and 17β-oestradiol, whilst HPGD silencing in parental MCF-7 cells reduced TAM sensitivity
TAMr cells released more prostaglandin E2 (PGE2) than controls, which was reduced in TAMr cells stably transfected with HPGD

Summary

Introduction

Due to its ability to bind to and modulate oestrogen receptor alpha (ERα) activity, Tamoxifen (TAM) was the first targeted therapy for breast cancer [1], with its widespread use in the clinic extending to four decades. Acquisition of TAM-resistance (TAMr) continues to be a major limitation for long-term management of breast cancer patients. In the last three decades, various groups have developed cell line models in order to help unravel the mechanistic basis of TAMr. In the last three decades, various groups have developed cell line models in order to help unravel the mechanistic basis of TAMr Most of these have been achieved through long term culture of the hormonesensitive MCF-7 human breast cancer cells in sub-lethal doses of TAM, during which resistant sub-clones develop after 3-6 months [4,5,6,7,8]. HPGD (EC 1.1.1.141) is a member of the short-chain alcohol (OH) dehydrogenase family and is the key NAD+-dependent enzyme responsible for the biological inactivation of prostaglandins, including prostaglandin E2 (PGE2), which is synthesized via the cyclooxygenase (COX) pathway

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