| First Author | Cortes E | Year | 2019 |
| Journal | EMBO Rep | Volume | 20 |
| Issue | 1 | PubMed ID | 30538116 |
| Mgi Jnum | J:269604 | Mgi Id | MGI:6273724 |
| Doi | 10.15252/embr.201846557 | Citation | Cortes E, et al. (2019) Tamoxifen mechanically reprograms the tumor microenvironment via HIF-1A and reduces cancer cell survival. EMBO Rep 20(1) |
| abstractText | 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. |
