Extracellular matrix–bound fgf2 mediates estrogen receptor signaling and therapeutic response in breast cancer

Josh W. DiGiacomo, Inês Godet, Michael Trautmann-Rodriguez, Daniele M. Gilkes

Research output: Contribution to journalArticlepeer-review

Abstract

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 (ERþ) 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. ERþ 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 ERþ 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 ERþ breast cancer cells to promote estrogen-independent ER signaling and resistance to endocrine therapy.

Original languageEnglish (US)
Pages (from-to)136-149
Number of pages14
JournalMolecular Cancer Research
Volume19
Issue number1
DOIs
StatePublished - Jan 1 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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