Estrogen activation by steroid sulfatase increases colorectal cancer proliferation via GPER

Lorna Gilligan, Habibur Rahman, Anne-Marie Hewitt, Alice Sitch, Alison Gondal, Anastasia Arvaniti, Angela Taylor, Martin Read, Dion Morton, Paul Foster

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)
164 Downloads (Pure)

Abstract

Context: Estrogens impact the incidence and progression of colorectal cancer (CRC) although precise molecular mechanisms remain ill-defined. Objective: Pre-receptor estrogen metabolism through steroid sulphatase (STS) and 17-hydroxysteroid dehydrogenase activity and subsequent non-genomic estrogen signaling in human CRC tissue, in the TCGA COAD dataset, and in in vitro and in vivo CRC models was investigated. The study aimed to define and therapeutically target pathways through which estrogens alter CRC proliferation and progression. Design, Setting, Patients, and Interventions: Human CRC samples with normal tissue matched-controls were collected from post-menopausal female and age-matched male patients. Estrogen metabolism enzymes and non-genomic downstream signaling pathways were determined. CRC cell lines were transfected with STS and cultured for in vitro and in vivo analysis. Estrogen metabolism was determined through a novel uHPLC-MS/MS method. Primary Outcome Measure: The proliferative effects of estrogen metabolism were evaluated using BRdU assays and in CRC mouse xenograft studies. Results: Human CRC exhibits dysregulated estrogen metabolism favoring estradiol synthesis. The activity of steroid sulfatase (STS), the fundamental enzyme that activates conjugated estrogens, is significantly (p<0.001) elevated in human CRC compared to matched controls. STS over-expression accelerates CRC proliferation in in vitro and in vivo models, with STS inhibition an effective treatment. Uniquely we define a G-protein coupled estrogen receptor (GPER) pro-proliferative pathway potentially through connective tissue growth factor (CTGF) in CRC. Conclusion: Human CRC favors estradiol synthesis to augment proliferation via GPER-stimulation. Further research is required on whether estrogen replacement therapy should be used with caution on patients at high-risk of developing CRC.
Original languageEnglish
Pages (from-to)4435-4447
JournalJournal of Clinical Endocrinology and Metabolism
Volume102
Issue number12
Early online date13 Sep 2017
DOIs
Publication statusPublished - 1 Dec 2017

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