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

Abstract

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.

Keywords: FGF/FGFR system; breast cancer; oncogenic signaling; targeted therapies; tumor microenvironment.

Figure 1

Schematic representation of aberrant FGF/FGFR signaling in breast cancer. The FGFR comprises three extracellular immunoglobulin-like subdomains (IgI, IgII, and IgIII), a transmembrane α-helix, and an intracellular bilobed cytoplasmic tyrosine kinase domain. IgI and IgII are separated by an acidic box. FGFs, which are secreted by tumor cells and/or the stromal compartment, bind to membrane-anchored FGFR monomers, then induce FGFR dimerization and the phosphorylation of the tyrosine kinase domains. The binding of FGFs to FGFRs is stabilized by heparan sulphate proteoglycans (HSPGs). Subsequently, the complex leads to the docking of adapter proteins and the activation of downstream pathways. For instance, ligand-stimulated FGFRs phosphorylate the FGFR-associated cytosolic docking protein FRS2. Once phosphorylated, FRS2 recruits Son of Sevenless adapter protein (SOS) and growth factor receptor-bound protein (GRB2) to activate rat sarcoma (RAS) and the downstream Rapidly Accelerated Fibrosarcoma (RAF) and MAPK/ERK Kinase (MEK) pathway. A different complex involves GRB2-associated binding protein 1 (GAB1), which recruits phosphoinositide 3-kinase (PI3K) that activates the Protein Kinase B (AKT) pathway. Phospholipase Cγ (PLCγ) hydrolyzes phosphatidylinositol-4,5-bisphosphate (PIP2) to phosphatidylinositol (3,4,5)-triphosphate (PIP3) and diacylglycerol (DAG). PIP3 releases calcium, whereas DAG activates protein kinase C, which helps to strengthen the activation of the MAPK pathway by phosphorylating RAF in a RAS-independent manner. Other cascades may also be activated by FGFRs, such as the signal transducer and activator of transcription (STAT)-dependent signaling. The aforementioned effectors regulate, in turn, gene expression as well as cell proliferation, migration, invasion, and angiogenesis. FGF/FGFR signaling may be down-regulated by receptor internalization or through negative regulators such as FGFR-like 1 (FGFRL1), with a similar expression to FGF (SEF), Sprouty (SPRY), Casitas B-lineage Lymphoma (CbL), and MAPK phosphatase 3 (MKP3).