Drug resistance to approved systemic therapies in estrogen receptor–positive (ER+) breast cancer remains common. We hypothesized that factors present in the human tumor microenvironment (TME) drive drug resistance. Screening of a library of recombinant secreted microenvironmental proteins revealed fibroblast growth factor 2 (FGF2) as a potent mediator of resistance to anti-estrogens, mTORC1 inhibition, and phosphatidylinositol 3-kinase inhibition in ER+ breast cancer. Phosphoproteomic analyses identified ERK1/2 as a major output of FGF2 signaling via FGF receptors (FGFRs), with consequent up-regulation of Cyclin D1 and down-regulation of Bim as mediators of drug resistance. FGF2-driven drug resistance in anti-estrogen–sensitive and –resistant models, including patient-derived xenografts, was reverted by neutralizing FGF2 or FGFRs. A transcriptomic signature of FGF2 signaling in primary tumors predicted shorter recurrence-free survival independently of age, grade, stage, and FGFR amplification status. These findings delineate FGF2 signaling as a ligand-based drug resistance mechanism and highlights an underdeveloped aspect of precision oncology: characterizing and treating patients according to their TME constitution.

雌激素受体阳性（ER +）乳腺癌对已批准的全身疗法的耐药性仍然很普遍。我们假设存在于人类肿瘤微环境（TME）中的因素驱动耐药性。重组分泌的微环境蛋白文库的筛选显示，成纤维细胞生长因子2（FGF2）是ER +乳腺癌中抗雌激素，mTORC1抑制和磷脂酰肌醇3激酶抑制的有效介体。磷酸蛋白质组学分析确定ERK1 / 2是通过FGF受体（FGFR）传递的FGF2信号的主要产物，因此，Cyclin D1的上调和Bim的下调是药物抗性的介质。通过中和FGF2或FGFR，可恢复抗雌激素敏感和耐药模型（包括患者来源的异种移植物）中FGF2驱动的耐药性。原发性肿瘤中FGF2信号的转录组学特征预示着无复发生存期的缩短，与年龄，等级，阶段和FGFR扩增状态无关。这些发现将FGF2信号转导为基于配体的耐药机制，并突显了精密肿瘤学的一个欠发达方面：根据患者的TME体质表征和治疗患者。