The extracellular matrix (ECM) is often unaccounted for in studies that consider the stromal contribution to cancer cell signaling and response to treatment. To investigate the influence of a fibrotic microenvironment, we use fibroblast-derived ECM scaffolds as a cell culture platform. 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. The ECM acts as a reservoir by binding, enriching, and presenting growth factors to adjacent epithelial cells. We identified FGF2 as a specific ECM-bound factor that drives ER signaling. ER+ cells cultured on ECM matrices have reduced sensitivity to ER-targeted therapies. The sensitivity to ER-targeted therapy can be restored by inhibiting FGF2–FGFR1 binding. ECM–FGF2 complexes promote Cyclin D1 induction that prevents G1 arrest even in the presence of antiestrogens. 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. Implications: This work uncovers how the ECM may mediate signaling between growth factors and ER+ breast cancer cells to promote estrogen-independent ER signaling and resistance to endocrine therapy.

中文翻译：

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细胞外基质结合的 FGF2 介导乳腺癌中的雌激素受体信号传导和治疗反应

在考虑基质对癌细胞信号传导和对治疗的反应的研究中，细胞外基质 (ECM) 通常下落不明。为了研究纤维化微环境的影响，我们使用成纤维细胞衍生的 ECM 支架作为细胞培养平台。我们发现，在 ECM 支架内培养的雌激素受体阳性 (ER+) 乳腺癌细胞通过依赖 MAPK 但不依赖雌激素的方式发生 ER 信号传导。ECM 通过将生长因子结合、富集和呈递给相邻的上皮细胞来充当储库。我们将 FGF2 确定为驱动 ER 信号传导的特定 ECM 结合因子。在 ECM 基质上培养的 ER+ 细胞对 ER 靶向治疗的敏感性降低。通过抑制 FGF2-FGFR1 结合可以恢复对 ER 靶向治疗的敏感性。ECM-FGF2 复合物促进 Cyclin D1 诱导，即使在抗雌激素存在的情况下也能防止 G1 停滞。这项工作表明 ECM 可以驱动 ER 信号传导和对内分泌治疗的抵抗，并表明具有高乳房 X 线照相乳腺密度的 ER+ 乳腺癌患者可能会受益于现有的 FGFR 靶向治疗。启示：这项工作揭示了 ECM 如何介导生长因子和 ER+ 乳腺癌细胞之间的信号传导，以促进雌激素非依赖性 ER 信号传导和对内分泌治疗的抵抗。并表明具有高乳房 X 光检查乳腺密度的 ER+ 乳腺癌患者可能会受益于现有的 FGFR 靶向治疗。启示：这项工作揭示了 ECM 如何介导生长因子和 ER+ 乳腺癌细胞之间的信号传导，以促进雌激素非依赖性 ER 信号传导和对内分泌治疗的抵抗。并表明具有高乳房 X 光检查乳腺密度的 ER+ 乳腺癌患者可能会受益于现有的 FGFR 靶向治疗。启示：这项工作揭示了 ECM 如何介导生长因子和 ER+ 乳腺癌细胞之间的信号传导，以促进雌激素非依赖性 ER 信号传导和对内分泌治疗的抵抗。