FGF/FGFR1 system in paired breast tumor-adjacent and tumor tissues, associations with mammographic breast density and tumor characteristics

INTRODUCTION: Mammographic breast density (MBD) is an established breast cancer risk factor, yet the underlying molecular mechanisms remain to be deciphered. Fibroblast growth factor receptor 1 (FGFR1) amplification is associated with breast cancer development and aberrant FGF signaling found in the biological processes related to both high mammographic density and breast cancer microenvironment. The aim of this study was to investigate the FGF/FGFR1 expression in-between paired tumor-adjacent and tumor tissues from the same patient, and its associations with MBD and tumor characteristics. METHODS: FGFR1 expression in paired tissues from 426 breast cancer patients participating in the Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA) cohort study was analyzed by immunohistochemistry. FGF ligand expression was obtained from RNA-sequencing data for 327 of the included patients. RESULTS: FGFR1 levels were differently expressed in tumor-adjacent and tumor tissues, with increased FGFR1 levels detected in 58% of the tumors. High FGFR1 expression in tumor tissues was associated with less favorable tumor characteristics; high histological grade (OR=1.86, 95% CI 1.00–3.44), high Ki67 proliferative index (OR=2.18, 95% CI 1.18–4.02) as well as tumors of Luminal B-like subtype (OR=2.56, 95%CI 1.29–5.06). While no clear association between FGFR1 expression and MBD was found, FGF ligand (FGF1, FGF11, FGF18) expression was positively correlated with MBD. DISCUSSION: Taken together, these findings support a role of the FGF/FGFR1 system in early breast cancer which warrants further investigation in the MBD–breast cancer context.