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

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

Abstrakti

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
Alkuperäiskielienglanti
Artikkeli46557
LehtiEMBO Reports
Vuosikerta20
Numero1
Sivumäärä22
ISSN1469-221X
DOI - pysyväislinkit
TilaJulkaistu - tammikuuta 2019
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

Tieteenalat

  • 217 Lääketieteen tekniikka
  • 1182 Biokemia, solu- ja molekyylibiologia

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