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Molecular Cancer Research
Molecular Cancer Research
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Signal Transduction and Functional Imaging

Extracellular Matrix–Bound FGF2 Mediates Estrogen Receptor Signaling and Therapeutic Response in Breast Cancer

Josh W. DiGiacomo, Inês Godet, Michael Trautmann-Rodriguez and Daniele M. Gilkes
Josh W. DiGiacomo
1Department of Chemical and Biomolecular Engineering and The Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, Maryland.
2Department of Oncology, Breast and Ovarian Cancer Program, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
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  • ORCID record for Josh W. DiGiacomo
Inês Godet
1Department of Chemical and Biomolecular Engineering and The Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, Maryland.
2Department of Oncology, Breast and Ovarian Cancer Program, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Michael Trautmann-Rodriguez
1Department of Chemical and Biomolecular Engineering and The Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, Maryland.
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Daniele M. Gilkes
1Department of Chemical and Biomolecular Engineering and The Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, Maryland.
2Department of Oncology, Breast and Ovarian Cancer Program, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
3Cellular and Molecular Medicine Program, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
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  • For correspondence: dgilkes1@jhu.edu
DOI: 10.1158/1541-7786.MCR-20-0554 Published January 2021
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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 (ER+) 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. ER+ 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 ER+ 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 ER+ breast cancer cells to promote estrogen-independent ER signaling and resistance to endocrine therapy.

This article is featured in Highlights of This Issue, p. 1

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2021;19:136–49

  • Received June 22, 2020.
  • Revision received August 21, 2020.
  • Accepted October 1, 2020.
  • Published first October 8, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Research: 19 (1)
January 2021
Volume 19, Issue 1
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Extracellular Matrix–Bound FGF2 Mediates Estrogen Receptor Signaling and Therapeutic Response in Breast Cancer
Josh W. DiGiacomo, Inês Godet, Michael Trautmann-Rodriguez and Daniele M. Gilkes
Mol Cancer Res January 1 2021 (19) (1) 136-149; DOI: 10.1158/1541-7786.MCR-20-0554

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Extracellular Matrix–Bound FGF2 Mediates Estrogen Receptor Signaling and Therapeutic Response in Breast Cancer
Josh W. DiGiacomo, Inês Godet, Michael Trautmann-Rodriguez and Daniele M. Gilkes
Mol Cancer Res January 1 2021 (19) (1) 136-149; DOI: 10.1158/1541-7786.MCR-20-0554
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