Tamoxifen mechanically reprograms the tumor microenvironment via HIF ‐1A and reduces cancer cell survival

Autor: Armando del Río Hernández, Dariusz Lachowski, Mariko Okada-Hatakeyama, Ernesto Cortes, Kazunari Iwamoto, Jaakko Teppo, Stephen D. Thorpe, Benjamin Robinson, Muge Sarper, Markku Varjosalo, David A. Lee, Tyler J Lieberthal
Přispěvatelé: Institute of Biotechnology, Molecular Systems Biology, Commission of the European Communities
Rok vydání: 2018
Předmět:
Estrogen receptor
Biochemistry
Receptors
G-Protein-Coupled
Mice
0302 clinical medicine
HIF‐1A
skin and connective tissue diseases
Cancer
0303 health sciences
Neovascularization
Pathologic
tamoxifen
Articles
Cellular Reprogramming
GPER
3. Good health
Gene Expression Regulation
Neoplastic
Receptors
Estrogen
Hormonal therapy
Carcinoma
Pancreatic Ductal
Signal Transduction
medicine.drug
Stromal cell
Cell Survival
Adenocarcinoma
Myosins
Article
03 medical and health sciences
Breast cancer
Cell Line
Tumor
Genetics
medicine
Animals
Humans
tumor microenvironment
Molecular Biology
030304 developmental biology
Tumor microenvironment
business.industry
0601 Biochemistry And Cell Biology
217 Medical engineering
Fibroblasts
Hypoxia-Inducible Factor 1
alpha Subunit
medicine.disease
Cancer research
1182 Biochemistry
cell and molecular biology
business
030217 neurology & neurosurgery
Tamoxifen
Developmental Biology
Zdroj: EMBO Reports
ISSN: 1469-3178
1469-221X
DOI: 10.15252/embr.201846557
Popis: 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.See also: E Cortes et al (January 2019) andM Pein & T Oskarsson (January 2019)EMBO Reports (2019) 20: e46557
Databáze: OpenAIRE
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