cancers Review The FGF/FGFR System in Breast Cancer: Oncogenic Features and Therapeutic Perspectives Maria Francesca Santolla and Marcello Maggiolini * Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy; [email protected] * Correspondence: [email protected] or [email protected] Received: 8 September 2020; Accepted: 16 October 2020; Published: 18 October 2020 Simple Summary: 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. 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: breast cancer; FGF/FGFR system; tumor microenvironment; oncogenic signaling; targeted therapies 1. Introduction Breast cancer is the most frequently diagnosed malignancy and the second leading cause of cancer death in women worldwide [1]. The high incidence of this disease, the complex mechanisms involved in its progression, as well as the resistance to chemotherapy underline the need to better elucidate the molecular features fueling breast tumors. Over the past few years, substantial advances have been made in the discovery of new drugs for the treatment of this malignancy. The improved understanding of breast cancer heterogeneity has allowed the development of more effective and individualized therapeutic approaches [2]. Nevertheless, only a limited number of targeted therapies have been approved and are currently used in breast cancer patients. In this context, anti-human epidermal Cancers 2020, 12, 3029; doi:10.3390/cancers12103029 www.mdpi.com/journal/cancers Cancers 2020, 12, 3029 2 of 20 growth factor receptor 2 (HER2) therapeutics such as trastuzumab, lapatinib, and pertuzumab have been proposed and used even in combination therapies [3–5]; nevertheless, the lack of responsiveness has been also observed [6]. Indeed, the intrinsic and acquired resistance to classical therapeutic agents and/or novel targeted drugs still represents a main problem in the treatment of breast cancer and a major cause of relapse and cancer death. Therefore, recent advances in the discovery of druggable kinase alterations are fostering the development of novel therapeutic strategies towards a better clinical management of breast cancer patients. In this context, the fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) system has recently attracted increasing interest due to its role in tumor growth, metastasis, and resistance to anti-cancer therapies [7,8]. For instance, aberrant FGF/FGFR activation may occur in both a ligand-dependent and ligand-independent manner in several tumors, including breast cancer [8–13]. Experimental and clinical evidence has also shown that deregulated FGF/FGFR signaling may elicit an oncogenic action [14–17], though some reports have indicated that the FGF/FGFR axis may exert an anticancer action in certain contexts [18,19]. Of note, various studies have emphasized the role of the transduction network triggered by the FGF/FGFR system towards a stimulatory interaction between tumor and stromal cells [20,21]. The aforementioned observations, together with the involvement of FGF/FGFR signaling in resistance to endocrine therapies [22,23], have suggested that the FGF/FGFR system may be considered a promising therapeutic target in order to establish more comprehensive anti-cancer strategies. Here, we recapitulate the recent discoveries regarding FGF/FGFR action in breast cancer. In particular, we focus on the FGFR genetic aberrations that may occur in breast cancer subtypes and the multifaceted interactions prompted by the FGF/FGFR axis in breast tumor stroma. In addition, we highlight the promising therapies targeting the FGF/FGFR system towards a better outcome for breast cancer patients. 2. The FGF/FGFR System 2.1. Receptors and Ligands The human FGFR family includes four highly conserved receptor tyrosine kinases (RTKs)—namely, FGFR1, FGFR2, FGFR3, and FGFR4—that are encoded by distinct genes, and an additional receptor named FGFR5 (also known as FGFRL1) which lacks the intracellular kinase domain [11]. On the basis of this peculiar feature, FGFR5 acts as a decoy receptor that, when binding to FGF ligands, may prevent their interaction with other FGFRs [24]. FGFR1-4 contain the classical extracellular domain, a transmembrane domainm and a tyrosine kinase cytoplasmic domain. The extracellular region encompasses three immunoglobulin-like subdomains (I, II, and III) and an acid box, which is typically located between the subdomains I and II, whereas the FGF ligand-binding site relies on the II and III subdomains [25]. The transmembrane region is made up of a single α-helix and the intracellular tyrosine kinase domain exhibits the canonical bilobed architecture of the protein kinases [26]. The FGF ligands belong to a family of 22 conserved molecules. The FGFs 1–10 and the FGFs 16–23 are secreted signaling molecules that interact with the FGFRs, while FGFs 11–14 do not act as FGFR ligands and their functions remain to be fully understood [11]. The FGF ligands can be classified into subfamilies according to the mechanism of action. Many FGFs act in an autocrine and/or paracrine manner, binding to FGFRs together with heparan sulfate proteoglycans (HSPGs), whereas FGF 19, FGF 21, and FGF 23 behave like endocrine ligands [27,28]. The endocrine FGFs lack the HSPG binding; consequently, they may diffuse from the site of production to the blood stream. Recruiting as cofactors certain members of the Klotho family, the endocrine FGFs contribute to maintaining whole-body homeostasis through FGFR-mediated signaling [29–31]. Cancers 2020, 12, 3029 3 of 20 2.2. FGF/FGFR Signaling Cascade Upon ligand activation, the FGFRs dimerize and the intracellular tyrosine kinase domains become phosphorylated and engage with various downstream proteins such as FGFR substrate 2 (FRS2), phospholipase Cγ (PLCγ), as well as diverse transduction pathways such as RAS-mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)–AKT, inositol-1,4,5-trisphosphate (IP3)–Ca2+, diacylglycerol (DAG)–protein kinase C (PKC) and Janus kinase–signal transducer and activator of transcription (JAK–STAT) [11]. Activated FGFRs localize to the cytoplasm, where they undergo lysosomal degradation or the recycling process, which are partially controlled by CbL-mediated monoubiquitylation or the LIS1/NDE1 complex [25,32]. FGFR signaling may be negatively regulated by MAPK phosphatase 3, Sprouty proteins, and SeF (similar expression to FGF, also known as IL17RD) family members [33–35] (Figure1). As the down-regulation of the activated receptors is an important process in order to prevent altered signaling, a defective FGFR ubiquitination system and/or an error in the mitigation pathway could induce aberrant cell growth and malignant transformation [36]. 3. FGFR Genetic Alterations in Breast Cancer FGFRs’ genetic alterations may contribute to tumor progression and poor outcomes in breast cancer patients. In this regard, an analysis performed in a cohort of 391 tumor patients has evidenced that FGF or FGFR aberrations are frequent in breast cancer (32.1%) and co-exist with other aberrations. For instance, univariate analysis identified in 15 genes certain anomalies associated with FGF/FGFR alterations [37]. A large next-generation sequencing analysis of approximately 5000 tumors showed that FGFR aberrations are harbored in about 7.1% of cancers [38]. Among the FGFR alterations, gene amplification has been found in an elevated percentage of cases (66%), however point mutations (26%) and chromosomal rearrangements (8%) have also been detected