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

Kevin Shee, Wei Yang, John W. Hinds, Riley A. Hampsch, Frederick S. Varn, Nicole A. Traphagen, Kishan Patel, Chao Cheng, Nicole P. Jenkins, Arminja N. Kettenbach, Eugene Demidenko, Philip Owens, Anthony C. Faber, Todd R. Golub, Ravid Straussman, Todd W. Miller

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)895-910
Number of pages16
JournalJournal of Experimental Medicine
Issue number3
StatePublished - Mar 2018

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology


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