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Updated: Feb 14, 2026

Live Imaging of Drug Responses in the Tumor Microenvironment in Mouse Models of Breast Cancer
08:26

Live Imaging of Drug Responses in the Tumor Microenvironment in Mouse Models of Breast Cancer

Published on: March 24, 2013

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

Kevin Shee1, Wei Yang1, John W Hinds1

  • 1Department of Molecular and Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH.

The Journal of Experimental Medicine
|February 14, 2018
PubMed

Insights

Fibroblast growth factor 2 (FGF2) drives resistance to common ER+ breast cancer therapies by altering tumor microenvironment signaling. Targeting FGF2 or its receptors (FGFRs) can overcome this resistance, improving treatment outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Drug resistance in estrogen receptor-positive (ER+) breast cancer limits treatment efficacy.
  • The tumor microenvironment (TME) is increasingly recognized for its role in mediating therapeutic resistance.

Purpose of the Study:

  • To investigate the role of secreted microenvironmental proteins in driving drug resistance in ER+ breast cancer.
  • To identify specific molecular pathways involved in FGF2-mediated resistance.

Main Methods:

  • Screening of secreted microenvironmental proteins.
  • Phosphoproteomic and transcriptomic analyses.
  • In vitro and in vivo models of ER+ breast cancer, including patient-derived xenografts.
  • Pharmacological inhibition of FGF2 and FGFRs.

Main Results:

  • Fibroblast growth factor 2 (FGF2) was identified as a key mediator of resistance to anti-estrogens, mTORC1, and PI3K inhibitors.
  • FGF2 signaling activates ERK1/2, leading to Cyclin D1 upregulation and Bim downregulation, thereby promoting resistance.
  • Neutralization of FGF2 or FGFRs reversed FGF2-driven drug resistance in various models.
  • A transcriptomic signature of FGF2 signaling predicted shorter recurrence-free survival in primary tumors.

Conclusions:

  • FGF2 signaling represents a significant ligand-driven mechanism of drug resistance in ER+ breast cancer.
  • Targeting the FGF2/FGFR pathway offers a potential therapeutic strategy to overcome resistance.
  • Characterizing the TME composition is crucial for personalized precision oncology in breast cancer treatment.

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