Tamoxifen mechanically reprograms the tumor microenvironment via HIF‐1A 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 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. Synopsis Tamoxifen biomechanically remodels the tumor microenvironment in pancreatic cancer independent of the nuclear estrogen receptors, but involving the GPER/HIF‐1A axis. Tamoxifen also reduces the ability of pancreatic cancer cells to survive under hypoxic conditions. Tamoxifen inhibits HIF‐1A through a hypoxia independent mechanism. Tamoxifen regulates the composition and organization of the ECM in pancreatic cancer. Tamoxifen suppresses the adaptive response of PDAC to hypoxia and increases vascular density. Graphical Abstract Tamoxifen biomechanically remodels the tumor microenvironment in pancreatic cancer independent of the nuclear estrogen receptors, but involving the GPER/HIF‐1A axis. Tamoxifen also reduces the ability of pancreatic cancer cells to survive under hypoxic conditions.