期刊
EMBO REPORTS
卷 20, 期 1, 页码 -出版社
WILEY
DOI: 10.15252/embr.201846557
关键词
GPER; HIF-1A; tamoxifen; tumor microenvironment
资金
- European Research Council (ERC) [282051 - ForceRegulation]
- Biotechnology and Biological Sciences Research Council (BBSRC) [BB/N018532/1]
- International Cooperative Research Program of Institute for Protein Research, Osaka University [ICRa-17-01]
- JSPS KAKENHI [15KT0084]
- Project for Cancer Research and Therapeutic Evolution (P-CREATE)
- AMED
- RIKEN Epigenome and Single Cell Project Grants
- Nagase Science Technology Foundation
- Astellas Foundation for Research on Metabolic Disorders
- James Dyson Foundation
- BBSRC [BB/N018532/1] Funding Source: UKRI
- Grants-in-Aid for Scientific Research [15KT0084] Funding Source: KAKEN
The tumor microenvironment is fundamental to cancer progression, and the influence of its mechanical properties is increasingly being appreciated. Tamoxifen has been used for many years to treat estrogen-positive breast cancer. Here we report that tamoxifen regulates the level and activity of collagen cross-linking and degradative enzymes, and hence the organization of the extracellular matrix, via a mechanism involving both the G protein-coupled estrogen receptor (GPER) and hypoxia-inducible factor-1 alpha (HIF-1A). We show that tamoxifen reduces HIF-1A levels by suppressing myosin-dependent contractility and matrix stiffness mechanosensing. Tamoxifen also downregulates hypoxia-regulated genes and increases vascularization in PDAC tissues. Our findings implicate the GPER/HIF-1A axis as a master regulator of peri-tumoral stromal remodeling and the fibrovascular tumor microenvironment and offer a paradigm shift for tamoxifen from a well-established drug in breast cancer hormonal therapy to an alternative candidate for stromal targeting strategies in PDAC and possibly other cancers.
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