Of the subtypes, the ER + subtype is the most commonly diagnosed type of breast cancer ( 2). For patients with breast cancer, the presence or absence of the estrogen receptor (ER), progesterone receptor (PR), or HER2 are important factors in subtype classification as well as for determining therapeutic options. Globally, breast cancer is the most commonly diagnosed type of cancer and the leading cause of cancer-related death among women ( 1). This work demonstrates that the ECM can drive ER signaling and resistance to endocrine therapy, and suggests that patients with ER + breast cancer that have high mammographic breast density may benefit from existing FGFR-targeted therapies. ECM–FGF2 complexes promote Cyclin D1 induction that prevents G 1 arrest even in the presence of antiestrogens. The sensitivity to ER-targeted therapy can be restored by inhibiting FGF2–FGFR1 binding. ER + cells cultured on ECM matrices have reduced sensitivity to ER-targeted therapies. We identified FGF2 as a specific ECM-bound factor that drives ER signaling. The ECM acts as a reservoir by binding, enriching, and presenting growth factors to adjacent epithelial cells. We uncover that estrogen receptor–positive (ER +) breast cancer cells cultured within ECM-scaffolds have an increase in ER signaling that occurs via an MAPK-dependent, but estrogen-independent manner.

To investigate the influence of a fibrotic microenvironment, we use fibroblast-derived ECM scaffolds as a cell culture platform. The extracellular matrix (ECM) is often unaccounted for in studies that consider the stromal contribution to cancer cell signaling and response to treatment.

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