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Mechanisms of FGFR3 actions in endocrine resistant breast cancer

D C Tomlinson1, M A Knowles, V Speirs

  • 1Section of Experimental Oncology, Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, LS9 7TF, United Kingdom. d.c.tomlinson@leeds.ac.uk

International Journal of Cancer
|July 28, 2011
PubMed

Insights

Fibroblast growth factor receptors (FGFRs) are implicated in breast cancer endocrine resistance. FGFR3 activation reduces sensitivity to tamoxifen and fulvestrant by activating MAPK and PI3K pathways, independent of estrogen receptor activity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Endocrinology

Background:

  • Endocrine therapy improves breast cancer treatment, but resistance and recurrence remain significant challenges, even in estrogen receptor (ER)-positive cases.
  • Understanding the molecular mechanisms of endocrine resistance is crucial for developing novel therapeutic strategies.
  • Fibroblast growth factor (FGF) and fibroblast growth factor receptor (FGFR) families are implicated in breast cancer development and progression.

Purpose of the Study:

  • To investigate the role of FGFRs in endocrine resistance in breast cancer.
  • To determine if FGFR activation impacts sensitivity to endocrine therapies like tamoxifen and fulvestrant.
  • To elucidate the signaling pathways involved in FGFR-mediated endocrine resistance.

Main Methods:

  • MCF7 cells were cultured with FGF1 to assess tamoxifen sensitivity in vitro.
  • Tissue microarrays were used to analyze FGFR3 expression in tamoxifen-resistant breast tumors.
  • Inducible activation systems and constitutively active FGFR3 mutants in MCF7 cells were employed to study the effects of FGFR3 activation on endocrine therapy response and downstream signaling pathways (MAPK, PI3K, phospholipase C gamma).

Main Results:

  • FGF1 treatment reduced tamoxifen sensitivity in MCF7 cells.
  • Increased FGFR3 expression was observed in tamoxifen-resistant breast tumors.
  • FGFR3 activation decreased sensitivity to tamoxifen and fulvestrant, independently of ER phosphorylation, and activated MAPK and PI3K pathways, with phospholipase C gamma activation being a key event.

Conclusions:

  • FGFR3 activation contributes to tamoxifen and fulvestrant resistance in ER-positive breast cancer.
  • FGFR3 signaling activates MAPK and PI3K pathways, key mediators of tamoxifen resistance.
  • FGFRs may play a significant role in both breast cancer development and resistance to endocrine therapy.

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