# The FGF/FGFR System in Breast Cancer: Oncogenic Features and Therapeutic Perspectives

**Authors:** Maria Francesca Santolla, Marcello Maggiolini

PMC · DOI: 10.3390/cancers12103029 · 2020-10-18

## TL;DR

This paper explores the role of the FGF/FGFR system in breast cancer and its potential as a new treatment target.

## Contribution

The paper provides a comprehensive overview of FGFR molecular aberrations and their therapeutic implications in breast cancer subtypes.

## Key findings

- FGFR molecular aberrations such as gene amplification and mutations are linked to breast cancer progression.
- FGF/FGFR signaling interacts with the tumor microenvironment in breast cancer.
- FGF/FGFR inhibitors show therapeutic potential in preclinical and clinical models.

## Abstract

The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) system represents an emerging therapeutic target in breast cancer. Here, we discussed previous studies dealing with FGFR molecular aberrations, the alterations in the FGF/FGFR signaling across the different subtypes of breast cancer, the functional interplay between the FGF/FGFR axis and important components of the breast microenvironment, the therapeutic usefulness of FGF/FGFR inhibitors for the treatment of breast cancer.

One of the major challenges in the treatment of breast cancer is the heterogeneous nature of the disease. With multiple subtypes of breast cancer identified, there is an unmet clinical need for the development of therapies particularly for the less tractable subtypes. Several transduction mechanisms are involved in the progression of breast cancer, therefore making the assessment of the molecular landscape that characterizes each patient intricate. Over the last decade, numerous studies have focused on the development of tyrosine kinase inhibitors (TKIs) to target the main pathways dysregulated in breast cancer, however their effectiveness is often limited either by resistance to treatments or the appearance of adverse effects. In this context, the fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) system represents an emerging transduction pathway and therapeutic target to be fully investigated among the diverse anti-cancer settings in breast cancer. Here, we have recapitulated previous studies dealing with FGFR molecular aberrations, such as the gene amplification, point mutations, and chromosomal translocations that occur in breast cancer. Furthermore, alterations in the FGF/FGFR signaling across the different subtypes of breast cancer have been described. Next, we discussed the functional interplay between the FGF/FGFR axis and important components of the breast tumor microenvironment. Lastly, we pointed out the therapeutic usefulness of FGF/FGFR inhibitors, as revealed by preclinical and clinical models of breast cancer.

## Linked entities

- **Genes:** FGFR (fibroblast growth factor receptor) [NCBI Gene 373310]
- **Proteins:** FGF (fibroblast growth factor), FGFR (fibroblast growth factor receptor)
- **Diseases:** breast cancer (MONDO:0004989)

## Full-text entities

- **Genes:** AHCYL1 (adenosylhomocysteinase like 1) [NCBI Gene 10768] {aka DCAL, IRBIT, PPP1R78, PRO0233, XPVKONA}, FGF21 (fibroblast growth factor 21) [NCBI Gene 26291], FRS2 (fibroblast growth factor receptor substrate 2) [NCBI Gene 10818] {aka FRS1A, FRS2A, FRS2alpha, SNT, SNT-1, SNT1}, Fgf7 (fibroblast growth factor 7) [NCBI Gene 14178] {aka Fgf5b, Kgf}, FGF7 (fibroblast growth factor 7) [NCBI Gene 2252] {aka HBGF-7, KGF}, Fgfr2 (fibroblast growth factor receptor 2) [NCBI Gene 14183] {aka Bek, Fgfr-2, Fgfr-7, Fgfr2b, Fgfr7, KGFR}, MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, AFF3 (ALF transcription elongation factor 3) [NCBI Gene 3899] {aka KINS, LAF4, MLLT2-like}, Fgf4 (fibroblast growth factor 4) [NCBI Gene 14175] {aka Fgf-4, Fgf7a, Fgfk, HBGF-4, Hst1, Hstf-1}, Pik3cg (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit gamma) [NCBI Gene 298947] {aka Pi3k}, Gab1 (GRB2-associated binding protein 1) [NCBI Gene 361388], CX3CR1 (C-X3-C motif chemokine receptor 1) [NCBI Gene 1524] {aka CCRL1, CMKBRL1, CMKDR1, GPR13, GPRV28, V28}, Cxcl5 (C-X-C motif chemokine ligand 5) [NCBI Gene 20311] {aka AMCF-II, Cxcl6, ENA-78, GCP-2, LIX, Scyb5}, CSF1R (colony stimulating factor 1 receptor) [NCBI Gene 1436] {aka BANDDOS, C-FMS, CD115, CSF-1R, CSFR, FIM2}, PAFAH1B1 (platelet activating factor acetylhydrolase 1b regulatory subunit 1) [NCBI Gene 5048] {aka LIS1, LIS2, MDCR, MDS, NudF, PAFAH}, AFF1 (ALF transcription elongation factor 1) [NCBI Gene 4299] {aka AF4, FEL, MLLT2, PBM1}, Frs2 (fibroblast growth factor receptor substrate 2) [NCBI Gene 314850], ERLIN2 (ER lipid raft associated 2) [NCBI Gene 11160] {aka C8orf2, Erlin-2, NET32, SPFH2, SPG18, SPG18A}, TXK (TXK tyrosine kinase) [NCBI Gene 7294] {aka BTKL, PSCTK5, PTK4, RLK, TKL}, Grb2 (growth factor receptor bound protein 2) [NCBI Gene 81504] {aka Ash-psi}, CCND1 (cyclin D1) [NCBI Gene 595] {aka BCL1, D11S287E, PRAD1, U21B31}, Fgfr4 (fibroblast growth factor receptor 4) [NCBI Gene 14186] {aka Fgfr-4}, TACC2 (transforming acidic coiled-coil containing protein 2) [NCBI Gene 10579] {aka AZU-1, ECTACC}, PRRT2 (proline rich transmembrane protein 2) [NCBI Gene 112476] {aka BFIC2, BFIS2, DSPB3, DYT10, EKD1, FICCA}, FGFR3 (fibroblast growth factor receptor 3) [NCBI Gene 2261] {aka ACH, CD333, CEK2, HSFGFR3EX, JTK4}, SLC45A3 (solute carrier family 45 member 3) [NCBI Gene 85414] {aka IPCA-2, IPCA-6, IPCA-8, IPCA6, PCANAP2, PCANAP6}, TP53 (tumor protein p53) [NCBI Gene 7157] {aka BCC7, BMFS5, LFS1, P53, TRP53}, KDR (kinase insert domain receptor) [NCBI Gene 3791] {aka CD309, FLK1, VEGFR, VEGFR2}, FGF1 (fibroblast growth factor 1) [NCBI Gene 2246] {aka AFGF, ECGF, ECGF-beta, ECGFA, ECGFB, FGF-1}, BAIAP2L1 (BAR/IMD domain containing adaptor protein 2 like 1) [NCBI Gene 55971] {aka IRTKS}, TACC3 (transforming acidic coiled-coil containing protein 3) [NCBI Gene 10460] {aka ERIC-1, ERIC1, Tacc4, maskin}, RET (ret proto-oncogene) [NCBI Gene 5979] {aka CDHF12, CDHR16, HSCR1, MEN2A, MEN2B, MTC1}, IL17RD (interleukin 17 receptor D) [NCBI Gene 54756] {aka HH18, IL-17RD, IL17RLM, SEF}, Cx3cr1 (C-X3-C motif chemokine receptor 1) [NCBI Gene 13051] {aka mCX3CR1}, PDGFRB (platelet derived growth factor receptor beta) [NCBI Gene 5159] {aka CD140B, IBGC4, IMF1, JTK12, KOGS, OPDKD}, KL (klotho) [NCBI Gene 9365] {aka HFTC3, KLA}, SDC2 (syndecan 2) [NCBI Gene 6383] {aka CD362, HSPG, HSPG1, SYND2}, Fgf2 (fibroblast growth factor 2) [NCBI Gene 14173] {aka Fgf-2, Fgf2a, Fgfb, bFGF}, FGFR4 (fibroblast growth factor receptor 4) [NCBI Gene 2264] {aka CD334, JTK2, TKF}, CBL (Cbl proto-oncogene) [NCBI Gene 867] {aka C-CBL, CBL2, FRA11B, NSLL, RNF55}, FGFRL1 (fibroblast growth factor receptor like 1) [NCBI Gene 53834] {aka FGFR-5, FGFR5, FHFR}, FGF19 (fibroblast growth factor 19) [NCBI Gene 9965], Fgfrl1 (fibroblast growth factor receptor-like 1) [NCBI Gene 360903] {aka Fgfr5}, Cd4 (CD4 antigen) [NCBI Gene 12504] {aka L3T4, Ly-4}, KIT (KIT proto-oncogene, receptor tyrosine kinase) [NCBI Gene 3815] {aka C-Kit, CD117, MASTC, PBT, SCFR}, Cxcl1 (C-X-C motif chemokine ligand 1) [NCBI Gene 14825] {aka Fsp, Gro1, KC, Mgsa, N51, Scyb1}, ERBB2 (erb-b2 receptor tyrosine kinase 2) [NCBI Gene 2064] {aka CD340, HER-2, HER-2/neu, HER2, MLN 19, MLN-19}, Fgf5 (fibroblast growth factor 5) [NCBI Gene 14176] {aka Fgf-5, Fgf3a, HBGF-5, angora, go}, Cx3cl1 (C-X3-C motif chemokine ligand 1) [NCBI Gene 20312] {aka ABCD-3, CX3C, Cxc3, D8Bwg0439e, FK, Scyd1}, PGR (progesterone receptor) [NCBI Gene 5241] {aka NR3C3, PR}, Erbb2 (erb-b2 receptor tyrosine kinase 2) [NCBI Gene 13866] {aka Erbb-2, HER-2, HER2, Neu, c-erbB2, c-neu}, Fgfr1 (fibroblast growth factor receptor 1) [NCBI Gene 14182] {aka Eask, FGFR-I, FLG, Fgfr-1, Flt-2, Fr1}, PIK3R1 (phosphoinositide-3-kinase regulatory subunit 1) [NCBI Gene 5295] {aka AGM7, GRB1, IMD36, p85, p85-ALPHA, p85alpha}, STAT3 (signal transducer and activator of transcription 3) [NCBI Gene 6774] {aka ADMIO, ADMIO1, APRF, HIES}, EREG (epiregulin) [NCBI Gene 2069] {aka EPR, ER, Ep}, FGF23 (fibroblast growth factor 23) [NCBI Gene 8074] {aka ADHR, FGFN, HFTC2, HPDR2, HYPF, PHPTC}, Akt1 (AKT serine/threonine kinase 1) [NCBI Gene 24185] {aka Akt}, FLT1 (fms related receptor tyrosine kinase 1) [NCBI Gene 2321] {aka FLT, FLT-1, VEGFR-1, VEGFR1}, Dusp6 (dual specificity phosphatase 6) [NCBI Gene 116663] {aka Mkp3}, FGFR1 (fibroblast growth factor receptor 1) [NCBI Gene 2260] {aka BFGFR, CD331, CEK, ECCL, FGFBR, FGFR-1}
- **Diseases:** Cancer- (MESH:D009369), non-small cell lung cancer (MESH:D002289), Breast Tumor (MESH:D001943), toxicity (MESH:D064420), lymph node and lung metastases (MESH:D008207), metastatic (MESH:D000092182), invasive ductal breast carcinoma (MESH:D018270), breast cancerogenesis (MESH:D061325), HR (MESH:D046150), hormone (MESH:C565870), RAF (MESH:D005354), mammary tumor (MESH:D015674), obese (MESH:D009765), Casitas B-lineage Lymphoma (MESH:D016393), lineage Lymphoma (MESH:D008223), bladder cancer (MESH:D001749), mammary tumorigenesis (MESH:D063646), metastases (MESH:D009362), glioblastoma (MESH:D005909), gastroesophageal carcinomas (MESH:D005764), TNBC (MESH:D064726), brain (MESH:D001927)
- **Chemicals:** tamoxifen (MESH:D013629), trastuzumab (MESH:D000068878), 3D185 (-), phosphatidylinositol (3,4,5)-triphosphate (MESH:C060974), anastrozole (MESH:D000077384), letrozole (MESH:D000077289), lapatinib (MESH:D000077341), palbociclib (MESH:C500026), E7080 (MESH:C531958), TAS-120 (MESH:C000713257), pertuzumab (MESH:C485206), BGJ398 (MESH:C568950), oxygen (MESH:D010100), FPA144 (MESH:C000714767), Debio-1347 (MESH:C000602562), IP3 (MESH:D015544), Erdafitinib (MESH:C000604580), PIP2 (MESH:D019269), NVP-BEZ235 (MESH:C531198), Dovitinib (MESH:C500007), Lucitanib (MESH:C000595232), DAG (MESH:D004075), metformin (MESH:D008687), BYL719 (MESH:C585539), AZD4547 (MESH:C572463), PD173074 (MESH:C115711), E3810 (MESH:D064750), fulvestrant (MESH:D000077267), MFGR1877S (MESH:C573866), calcium (MESH:D002118)
- **Species:** Homo sapiens (human, species) [taxon 9606], Mus musculus (house mouse, species) [taxon 10090]
- **Mutations:** S125L, glycine (G) into an arginine (R), rs17182023, rs2981579, R203C, rs351855, V550E, K566R, rs2981582, rs2420946, rs1219648, rs1966265, rs2981578
- **Cell lines:** SUM185PE — Homo sapiens (Human), Breast ductal carcinoma, Cancer cell line (CVCL_5591)

## Figures

1 figure with captions in the complete paper: https://tomesphere.com/paper/PMC7603197/full.md

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Source: https://tomesphere.com/paper/PMC7603197