eprintid: 10065185
rev_number: 22
eprint_status: archive
userid: 608
dir: disk0/10/06/51/85
datestamp: 2019-01-08 09:26:09
lastmod: 2021-09-19 22:34:51
status_changed: 2019-01-08 09:26:09
type: article
metadata_visibility: show
creators_name: Cortes, E
creators_name: Lachowski, D
creators_name: Rice, A
creators_name: Thorpe, SD
creators_name: Robinson, B
creators_name: Yeldag, G
creators_name: Lee, DA
creators_name: Ghemtio, L
creators_name: Rombouts, K
creators_name: Del Río Hernández, AE
title: Tamoxifen mechanically deactivates hepatic stellate cells via the G protein-coupled estrogen receptor
ispublished: inpress
divisions: UCL
divisions: B02
divisions: C10
divisions: D17
divisions: G91
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abstract: Tamoxifen has been used for many years to target estrogen receptor signalling in breast cancer cells. Tamoxifen is also an agonist of the G protein-coupled estrogen receptor (GPER), a GPCR ubiquitously expressed in tissues that mediates the acute response to estrogens. Here we report that tamoxifen promotes mechanical quiescence in hepatic stellate cells (HSCs), stromal fibroblast-like cells whose activation triggers and perpetuates liver fibrosis in hepatocellular carcinomas. This mechanical deactivation is mediated by the GPER/RhoA/myosin axis and induces YAP deactivation. We report that tamoxifen decreases the levels of hypoxia-inducible factor-1 alpha (HIF-1α) and the synthesis of extracellular matrix proteins through a mechanical mechanism that involves actomyosin-dependent contractility and mechanosensing of tissue stiffness. Our results implicate GPER-mediated estrogen signalling in the mechanosensory-driven activation of HSCs and put forward estrogenic signalling as an option for mechanical reprogramming of myofibroblast-like cells in the tumour microenvironment. Tamoxifen, with half a century of safe clinical use, might lead this strategy of drug repositioning.
date: 2019
date_type: published
official_url: https://doi.org/10.1038/s41388-018-0631-3
oa_status: green
full_text_type: pub
language: eng
primo: open
primo_central: open_green
article_type_text: Journal Article
verified: verified_manual
elements_id: 1616671
doi: 10.1038/s41388-018-0631-3
pii: 10.1038/s41388-018-0631-3
lyricists_name: Rombouts, Krista
lyricists_id: KROMB89
actors_name: Bracey, Alan
actors_id: ABBRA90
actors_role: owner
full_text_status: public
publication: Oncogene
event_location: England
issn: 1476-5594
citation:        Cortes, E;    Lachowski, D;    Rice, A;    Thorpe, SD;    Robinson, B;    Yeldag, G;    Lee, DA;             ... Del Río Hernández, AE; + view all <#>        Cortes, E;  Lachowski, D;  Rice, A;  Thorpe, SD;  Robinson, B;  Yeldag, G;  Lee, DA;  Ghemtio, L;  Rombouts, K;  Del Río Hernández, AE;   - view fewer <#>    (2019)    Tamoxifen mechanically deactivates hepatic stellate cells via the G protein-coupled estrogen receptor.                   Oncogene        10.1038/s41388-018-0631-3 <https://doi.org/10.1038/s41388-018-0631-3>.    (In press).    Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10065185/1/s41388-018-0631-3.pdf