Abstract
Triple-negative breast cancer (TNBC) is an aggressive breast tumor subtype characterized by poor clinical outcome. In recent years, numerous advancements have been made to better understand the biological landscape of TNBC, though appropriate targets still remain to be determined. In the present study, we have determined that the expression levels of FGF2 and S100A4 are higher in TNBC with respect to non-TNBC patients when analyzing “The Invasive Breast Cancer Cohort of The Cancer Genome Atlas” (TCGA) dataset. In addition, we have found that the gene expression of FGF2 is positively correlated with S100A4 in TNBC samples. Performing quantitative PCR, Western blot, CRISPR/Cas9 genome editing, promoter studies, immunofluorescence analysis, subcellular fractionation studies, and ChIP assays, we have also demonstrated that FGF2 induces in TNBC cells the upregulation and secretion of S100A4 via FGFR1, along with the ERK1/2–AKT–c-Rel transduction signaling. Using conditioned medium from TNBC cells stimulated with FGF2, we have also ascertained that the paracrine activation of the S100A4/RAGE pathway triggers angiogenic effects in vascular endothelial cells (HUVECs) and promotes the migration of cancer-associated fibroblasts (CAFs). Collectively, our data provide novel insights into the action of the FGF2/FGFR1 axis through S100A4 toward stimulatory effects elicited in TNBC cells.
Highlights
Breast cancer is the most frequently diagnosed tumor and represents the second leading cause of cancer death among females worldwide [1]
We have provided novel findings regarding the role of the FGF2/FGFR1 transduction pathway on the regulation of S100 calcium-binding protein A4 (S100A4) in triple-negative breast cancer (TNBC) cells
Querying the public The Cancer Genome Atlas” (TCGA) dataset, we first ascertained that the expression of S100A4 is higher in TNBC with respect to non-TNBC patients and correlated with the levels of FGF2 in TNBC samples
Summary
Breast cancer is the most frequently diagnosed tumor and represents the second leading cause of cancer death among females worldwide [1] To date, it has been identified different subgroups of breast cancers with peculiar prognosis and response to chemotherapeutics [2,3,4,5,6,7]. In the last years, great efforts have been made toward the identification of signaling pathways contributing to the TNBC progression [12,13,14] In this regard, fibroblast growth factor (FGF)/FGF receptor (FGFR) axis has been indicated as a potential candidate for targeted therapy [15,16,17]. It is worth mentioning that TNBC cells may show genomic FGFR alterations along with an altered FGF2 signaling loop, suggesting that FGFR inhibitors and monoclonal antibodies could be considered in comprehensive therapeutic approaches aimed to halt TNBC progression [25,26]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call