5 research outputs found
Tamoxifen mechanically reprograms the tumor microenvironment via HIFâ1A and reduces cancer cell survival
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 estrogenâpositive breast cancer. Here we report that tamoxifen regulates the level and activity of collagen crossâlinking and degradative enzymes, and hence the organization of the extracellular matrix, via a mechanism involving both the G proteinâcoupled estrogen receptor (GPER) and hypoxiaâinducible factorâ1 alpha (HIFâ1A). We show that tamoxifen reduces HIFâ1A levels by suppressing myosinâdependent contractility and matrix stiffness mechanosensing. Tamoxifen also downregulates hypoxiaâregulated genes and increases vascularization in PDAC tissues. Our findings implicate the GPER/HIFâ1A axis as a master regulator of periâtumoral stromal remodeling and the fibrovascular tumor microenvironment and offer a paradigm shift for tamoxifen from a wellâestablished 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: e46557Peer reviewe