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FGFR4 in endocrine resistance: overexpression and estrogen regulation without direct causative role

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Abstract

Purpose

Endocrine therapy resistance is the major challenge of managing patients with estrogen receptor positive (ER+) breast cancer. We previously reported frequent overexpression of FGFR4 in endocrine-resistant cell lines and breast cancers that recurred and metastasized following endocrine therapy, suggesting FGFR4 as a potential driver of endocrine resistance. In this study, we investigated the role of FGFR4 in mediating endocrine resistance and explored the therapeutic potential of targeting FGFR4 in advanced breast cancer.

Methods

A gene expression signature of FGFR4 activity was examined in ER+breast cancer pre- and post-neoadjuvant endocrine therapy and the association between FGFR4 expression and patient survival was examined. A correlation analysis was used to uncover potential regulators of FGFR4 overexpression. To investigate if FGFR4 is necessary to drive endocrine resistance, we tested response to FGFR4 inhibition in long-term estrogen-deprived (LTED) cells and their paired parental cells. Doxycycline inducible FGFR4 overexpression and knockdown cell models were generated to examine if FGFR4 was sufficient to confer endocrine resistance. Finally, we examined response to FGFR4 monotherapy or combination therapy with fulvestrant in breast cancer cell lines to explore the potential of FGFR4 targeted therapy for advanced breast cancer and assessed the importance of PAM50 subtype in response to FGFR4 inhibition.

Results

A FGFR4 activity gene signature was significantly upregulated post-neoadjuvant aromatase inhibitor treatment, and high FGFR4 expression predicted poorer survival in patients with ER+breast cancer. Gene expression association analysis using TCGA, METABRIC, and SCAN-B datasets uncovered ER as the most significant gene negatively correlated with FGFR4 expression. ER negatively regulates FGFR4 expression at both the mRNA and protein level across multiple ER+breast cancer cell lines. Despite robust overexpression of FGFR4, LTED cells did not show enhanced responses to FGFR4 inhibition compared to parental cells. Similarly, FGFR4 overexpression and knockdown did not substantially alter response to endocrine treatment in ER+cell lines, nor did FGFR4 and fulvestrant combination treatment show synergistic effects. The HER2-like subtype of breast cancer showed elevated expression of FGFR4 and an increased response to FGFR4 inhibition relative to other breast cancer subtypes.

Conclusions

Despite ER-mediated upregulation of FGFR4 post-endocrine therapy, our study does not support a general role of FGFR4 in mediating endocrine resistance in ER+breast cancer. The significant upregulation of FGFR4 expression in treatment-resistant clinical samples and models following endocrine therapy does not necessarily establish a causal link between the gene and treatment response. Our data suggest that specific genomic backgrounds such as HER2 expression may be required for FGFR4 function in breast cancer and should be further explored.

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Data availability

No datasets were generated or analysed during the current study.

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Acknowledgements

We would like to thank The Cancer Genome Atlas (TCGA) Research Network (https://www.cancer.gov/tcga), the Sweden Cancerome Analysis Network, and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) for generating and sharing their data to empower our study. We appreciate technical support from Jian Chen and Loise Mazur, and support from personnel the Department of Pathology at Magee Womens Hospital, and the Pittsburgh Biospecimen Core (PBC). We are grateful to Blueprint Medicines (BPMC) and H3 Biomedicine for providing BLU554 and H3B-6527, respectively.

Funding

This work was supported in part by NIH R01 CA224909 (to SO), Susan G Komen (SAC160073 SO), Shear Family Foundation, Magee Womens Research Institute and Foundation, and by UPMC Hillman Cancer Center and Tissue and Research Pathology/Pitt Biospecimen Core and the Biostatistics Core shared resources, which are supported in part by award P30CA047904.

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Authors and Affiliations

  1. Womens Cancer Research Center at UPMC Hillman Cancer Center, Magee Women’S Research Institute, 5051 Center Ave, Pittsburgh, PA, 15213, USA

    Kai Ding, Lyuqin Chen, Kevin M. Levine, Matthew J. Sikora, Nilgun Tasdemir, David Dabbs, Rachel Jankowitz, Osama Shah, Jenny Atkinson, Adrian V. Lee & Steffi Oesterreich

  2. Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA

    Adrian V. Lee

  3. Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA

    Lyuqin Chen, Matthew J. Sikora, Nilgun Tasdemir, Jenny Atkinson, Adrian V. Lee & Steffi Oesterreich

  4. Integrative Systems Biology Program, University of Pittsburgh, Pittsburgh, PA, USA

    Kai Ding & Osama Shah

  5. Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA

    Kevin M. Levine

  6. Magee Womens Hospital, Pittsburgh, PA, USA

    David Dabbs & Rachel Jankowitz

  7. Albert Einstein College of Medicine, New York, NY, USA

    Rachel Hazan

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Contributions

All authors contributed to the study design and the preparation of the manuscript. K.D., L.C., K.L., and O.S. conducted the studies under the guidance of J.A., A.V.L. and S.O. M.S., N.T., D.D., R.J. and R.H. provided models and clinical data essential for this study.

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Correspondence to Steffi Oesterreich.

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Ding, K., Chen, L., Levine, K.M. et al. FGFR4 in endocrine resistance: overexpression and estrogen regulation without direct causative role. Breast Cancer Res Treat 211, 501–515 (2025). https://doi.org/10.1007/s10549-025-07666-x

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