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

Ernesto Cortes, Dariusz Lachowski, Benjamin Robinson, Muge Sarper, Jaakko S Teppo, Stephen D Thorpe, Tyler J Lieberthal, Kazunari Iwamoto, David A Lee, Mariko Okada‐Hatakeyama, Markku T Varjosalo, Armando E del Río Hernández

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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
Original languageEnglish
Article number46557
JournalEMBO Reports
Issue number1
Number of pages22
Publication statusPublished - Jan 2019
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 217 Medical engineering
  • 1182 Biochemistry, cell and molecular biology

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