Extracellular Matrix-Bound FGF2 Mediates Estrogen Receptor Signaling and Therapeutic Response in Breast Cancer.

摘要: The extracellular matrix (ECM) is often unaccounted for in studies that consider the stromal contribution to cancer cell signaling and response treatment. To investigate influence of a fibrotic microenvironment, we use fibroblast-derived ECM scaffolds as culture platform. We uncover estrogen receptor-positive (ER+) breast cells cultured within ECM-scaffolds have an increase ER occurs via MAPK-dependent, but estrogen-independent manner. acts reservoir by binding, enriching, presenting growth factors adjacent epithelial cells. identified FGF2 specific ECM-bound factor drives signaling. ER+ on matrices reduced sensitivity ER-targeted therapies. therapy can be restored inhibiting FGF2-FGFR1 binding. ECM-FGF2 complexes promote Cyclin D1 induction prevents G1 arrest even presence antiestrogens. This work demonstrates drive resistance endocrine therapy, suggests patients with high mammographic density may benefit from existing FGFR-targeted IMPLICATIONS: uncovers how mediate between therapy.