Therapeutically targeting tumor microenvironment-mediated drug resistance in estrogen receptor-positive breast cancer

J Exp Med. 2018 Mar 5;215(3):895-910. doi: 10.1084/jem.20171818. Epub 2018 Feb 7.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Bcl-2-Like Protein 11 / metabolism
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclin D1 / metabolism
  • Cytokines / metabolism
  • Down-Regulation / drug effects
  • Drug Resistance, Neoplasm* / drug effects
  • Female
  • Fibroblast Growth Factor 2 / pharmacology
  • Humans
  • Ligands
  • Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice
  • Models, Biological
  • Molecular Targeted Therapy*
  • Neoplasm Recurrence, Local / pathology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Receptors, Estrogen / metabolism*
  • Receptors, Fibroblast Growth Factor / metabolism
  • Signal Transduction
  • Transcriptome / genetics
  • Treatment Outcome
  • Tumor Microenvironment* / drug effects
  • Up-Regulation / drug effects


  • Bcl-2-Like Protein 11
  • Cytokines
  • Ligands
  • Phosphoinositide-3 Kinase Inhibitors
  • Receptors, Estrogen
  • Receptors, Fibroblast Growth Factor
  • Fibroblast Growth Factor 2
  • Cyclin D1
  • Mechanistic Target of Rapamycin Complex 1