Paradoxical cancer cell proliferation after FGFR inhibition through decreased p21 signaling in FGFR1-amplified breast cancer cells

• Published in: Breast cancer research : BCR Vol. 26; no. 1; p. 54
• Main Authors: Chi, Feng, Griffiths, Jason I, Nath, Aritro, Bild, Andrea H
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 29.03.2024; BioMed Central; BMC
• Subjects: Analysis; Antibiotics; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cancer cells; Cancer therapies; Cell cycle; Cell growth; Cell Line, Tumor; Cell Proliferation; Clinical trials; Cyclin-dependent kinase inhibitor p21; Cyclin-dependent kinases; Drug dosages; Female; FGF2; FGFR1; Fibroblast growth factor 2; Fibroblast Growth Factor 2 - metabolism; Fibroblast Growth Factor 2 - pharmacology; Fibroblast Growth Factor 2 - therapeutic use; Fibroblast growth factor receptor 1; Fibroblast growth factor receptors; Fibroblast growth factors; Fibroblast Growth Factors - pharmacology; Genes; Humans; JAK-STAT; Janus Kinases - metabolism; Janus Kinases - pharmacology; Janus Kinases - therapeutic use; Kinases; Ligands; MAP kinase; Mediation; Medical prognosis; p21; Patients; Phase transitions; Prognosis; Proteins; Receptor, Fibroblast Growth Factor, Type 1; S phase; Signal Transduction; Spheroids; STAT Transcription Factors - metabolism; STAT Transcription Factors - pharmacology; STAT Transcription Factors - therapeutic use; Stem cells; Stemness; Transcriptomes; Stemness; JAK-STAT; FGF2; p21; FGFR1
• ISSN: 1465-542X; 1465-5411; 1465-542X
• DOI: 10.1186/s13058-024-01808-7

Fibroblast growth factors (FGFs) control various cellular functions through fibroblast growth factor receptor (FGFR) activation, including proliferation, differentiation, migration, and survival. FGFR amplification in ER + breast cancer patients correlate with poor prognosis, and FGFR inhibitors are currently being tested in clinical trials. By comparing three-dimensional spheroid growth of ER + breast cancer cells with and without FGFR1 amplification, our research discovered that FGF2 treatment can paradoxically decrease proliferation in cells with FGFR1 amplification or overexpression. In contrast, FGF2 treatment in cells without FGFR1 amplification promotes classical FGFR proliferative signaling through the MAPK cascade. The growth inhibitory effect of FGF2 in FGFR1 amplified cells aligned with an increase in p21, a cell cycle inhibitor that hinders the G1 to S phase transition in the cell cycle. Additionally, FGF2 addition in FGFR1 amplified cells activated JAK-STAT signaling and promoted a stem cell-like state. FGF2-induced paradoxical effects were reversed by inhibiting p21 or the JAK-STAT pathway and with pan-FGFR inhibitors. Analysis of patient ER + breast tumor transcriptomes from the TCGA and METABRIC datasets demonstrated a strong positive association between expression of FGF2 and stemness signatures, which was further enhanced in tumors with high FGFR1 expression. Overall, our findings reveal a divergence in FGFR signaling, transitioning from a proliferative to stemness state driven by activation of JAK-STAT signaling and modulation of p21 levels. Activation of these divergent signaling pathways in FGFR amplified cancer cells and paradoxical growth effects highlight a challenge in the use of FGFR inhibitors in cancer treatment.