# FGFR4: A druggable mediator of endocrine resistance in breast cancer

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $354,577

## Abstract

~30,000 new cases of invasive lobular breast cancer (ILC) diagnosed per year make ILC the 6th most common
cancer in women. ILC is treated almost identically to the more common invasive ductal cancer (IDC), despite
differences in clinical presentation and tumor biology, including the near universal loss of E-cadherin. Although
ILCs show better prognostic markers than IDC, such as high rates of estrogen receptor (ER) positivity and low
proliferation, patients with ILC often develop resistance to endocrine therapy and in the long term suffer more
recurrences than IDC. Our long-term goal is to improve outcome for patients with ILC, a disease associated
with limited understanding and representing a great unmet clinical need.
To understand mechanisms driving ILC endocrine resistance, we developed endocrine-resistant ILC cell line
models, and collected endocrine resistant metastatic breast cancer samples, and unbiased transcriptomic
profiling led to the identification of fibroblast growth factor receptor 4 (FGFR4) as the most overexpressed
gene. Analysis of publicly available databases lead to identification of hotspot FGFR4 mutations. Lack of
consistent overexpression of FGFR1-3 in endocrine resistant models and metastatic tissues strongly suggests
a unique and previously unappreciated role for FGFR4 that warrants further study. While FGFR4
overexpression and mutations are observed in both IDC and ILC, they are significantly enriched in ILC. This
suggests that the unique genetic background of ILC, including the well-known loss of E-cadherin but also the
more recently identified activation of ERBB2/ERBB3, may provide a permissive environment for FGFR4
signaling. Functionally, FGFR4 loss or inhibition results in altered expression of ER target genes and
decreased growth and colony formation. Finally, preliminary studies of combined FGFR4 and ER targeting
confer synergistic growth inhibition. We therefore hypothesize that the unique genetic background of ILC
creates a permissive environment for FGFR4 signaling to mediate endocrine resistance, and that the
combination of FGFR4 inhibition and endocrine therapy represents a novel treatment strategy.
In the current study, we will i) determine how FGFR4 causes endocrine resistance in breast cancer, and ii)
examine whether key genomic features of primary and metastatic breast cancer cross-talk and enhance
FGFR4 signaling and activity, and iii) credential FGFR4 as a druggable target in breast cancer therapy by
defining biomarkers.
Our collaborative team with expertise in molecular biology, biostatistics/bioinformatics, pathology and medical
oncology will utilize unique models, valuable clinical samples, promising drugs that are already in trials, and
innovative approaches and tools to test our focused hypotheses on a novel role of FGFR4 in endocrine
resistance. We expect to gain fundamental knowledge of how the readily druggable ER-FGFR4 axis signals in
ILC and!to assess FGFR4 inhibition as a novel treatment str...

## Key facts

- **NIH application ID:** 9827554
- **Project number:** 5R01CA224909-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Steffi Oesterreich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $354,577
- **Award type:** 5
- **Project period:** 2017-12-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9827554

## Citation

> US National Institutes of Health, RePORTER application 9827554, FGFR4: A druggable mediator of endocrine resistance in breast cancer (5R01CA224909-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9827554. Licensed CC0.

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