Abstract
Context:Estrogens affect the incidence and progression of colorectal cancer (CRC), although the precise molecular mechanisms remain ill-defined.Objective:The present study investigated prereceptor estrogen metabolism through steroid sulphatase (STS) and 17β-hydroxysteroid dehydrogenase activity and subsequent nongenomic estrogen signaling in human CRC tissue, in The Cancer Genome Atlas colon adenocarcinoma data set, and in in vitro and in vivo CRC models. We 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 postmenopausal female and age-matched male patients. Estrogen metabolism enzymes and nongenomic 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 using an ultra-performance liquid chromatography–tandem mass spectrometry method.Primary Outcome Measure:The proliferative effects of estrogen metabolism were evaluated using 5-bromo-2′-deoxyuridine assays and CRC mouse xenograft studies.Results:Human CRC exhibits dysregulated estrogen metabolism, favoring estradiol synthesis. The activity of STS, the fundamental enzyme that activates conjugated estrogens, is significantly (P < 0.001) elevated in human CRC compared with matched controls. STS overexpression accelerates CRC proliferation in in vitro and in vivo models, with STS inhibition an effective treatment. We defined a G-protein–coupled estrogen receptor (GPER) proproliferative pathway potentially through increased expression of connective tissue growth factor in CRC.Conclusion:Human CRC favors estradiol synthesis to augment proliferation via GPER stimulation. Further research is required regarding whether estrogen replacement therapy should be used with caution in patients at high risk of developing CRC.
Highlights
Context: Estrogens affect the incidence and progression of colorectal cancer (CRC), the precise molecular mechanisms remain ill-defined
The present study investigated prereceptor estrogen metabolism through steroid sulphatase (STS) and 17b-hydroxysteroid dehydrogenase activity and subsequent nongenomic estrogen signaling in human CRC tissue, in The Cancer Genome Atlas colon adenocarcinoma data set, and in in vitro and in vivo CRC models
Further research is required regarding whether estrogen replacement therapy should be used with caution in patients at high risk of developing CRC. (J Clin Endocrinol Metab 102: 4435–4447, 2017)
Summary
Experimental proceduresCompounds STX64 (Irosustat) was from Sigma-Aldrich, Ltd. (Dorset, UK) and Professor Barry Potter, University of Oxford. Compounds STX64 (Irosustat) was from Sigma-Aldrich, Ltd. (Dorset, UK) and Professor Barry Potter, University of Oxford. G1 and G15 were from Torcis Bioscience (Abingdon, UK). E1S, E1, E2S, and E2 were from Sigma-Aldrich. Human tissue and cell culture Matched normal and cancerous human colorectal tissue was obtained with local ethics committee approval and informed patient consent. CRC samples from patients with genetic predisposition to CRC, such as familial adenomatous polyposis and hereditary nonpolyposis CRC were excluded. The patient characteristics and disease stage are outlined in Supplemental Table 1
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