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.

Targeted Sequencing of Taiwanese Breast Cancer with Risk Stratification by the Concurrent Genes Signature: A Feasibility Study

“…FGFR1 amplification (8p12) is one of the most common focal amplifications in breast cancer (around 10%), especially for the ER-positive phenotype. Overexpression of FGFR1 is induced by cyclin D1 via the pRb/E2F pathway, while cyclin D1 is overexpressed in human malignancies and correlates with poor prognosis [ 32 ]. As an oncogene, FGFR1 deletion is less understood, while FGFR2 (10q26) missense mutation may be indicative of anti-FGFR2 inhibitor, as amplification or overexpression of FGFR2 was observed in 4% of triple negative breast cancers [ 33 ].…”

SIRT2 promotes murine melanoma progression through natural killer cell inhibition

“…SIRT2’s established roles in inflammation and glucose and iron metabolism, all known regulators of tumor progression 7 , 12 – 15 , indicate that systemic and microenvironment SIRT2, rather than just expression in tumor cells, might have implications on progression of tumors once they have already undergone tumorigenesis. The tumor microenvironment (TME), with effects on angiogenesis, immune response, and fibroblast growth factor, is an established major determinant of long-term tumor progression 16 – 18 . One such example is PTEN, a well-known tumor suppressor, that inhibits tumor cell growth in tumor cell, also suppresses breast tumor progression through stromal fibroblasts 19 , 20 .…”

S100A4 Is Involved in Stimulatory Effects Elicited by the FGF2/FGFR1 Signaling Pathway in Triple-Negative Breast Cancer (TNBC) Cells

“…S100A4 levels were found upregulated by FGF2 in conditioned medium derived from FGFR1 (WT) MDA-MB-231 and SUM159 cells, but not in conditioned medium derived from FGFR1 (KO) MDA-MB-231 and SUM159 cells treated with FGF2 (Figure 2i,j). Considering that FGFR1 activation by FGF2 triggers certain transduction pathways [59,60], we assessed that the upregulation of S100A4 induced by FGF2 is prevented using the MEK inhibitor PD98059 and the PI3K inhibitor Wortmannin (WM) (Figure 2k,l), but not in the presence of the STAT3 inhibitor STA21 and the JNK inhibitor SP600125 (SP) (data not shown). In support of these findings, the treatment with FGF2 induced the phosphorylation of FGFR1 as well as the activation of ERK1/2 and AKT in MDA-MB-231 and SUM159 cells (Supplementary Figure S2a,b).…”