FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer

摘要

Amplification of FGFR1 occurs in approximately 10% of breast cancers and is associated with poor prognosis. However, it is uncertain whether over-expression of FGFR1 is causally linked to the poor prognosis of amplified cancers. Here, we show that FGFR1 over-expression is robustly associated with FGFR1 amplification in two independent series of breast cancers. Breast cancer cell lines with FGFR1 over-expression, and amplification, show enhanced ligand dependent signalling, with increased activation of the MAPK and PI3K-AKT signalling pathways in response to FGF2, but also show basal ligand independent signalling, and are dependent on FGFR signalling for anchorage independent growth. FGFR1 amplified cell lines demonstrate resistance to 4-OH-Tamoxifen, that is reversed by siRNA silencing of FGFR1, suggesting that FGFR1 over-expression also promotes endocrine therapy resistance. FGFR1 signalling suppresses progesterone receptor (PR) expression in vitro and likewise amplified cancers are frequently PR negative, identifying a potential biomarker for FGFR1 activity. Furthermore, we show that amplified cancers have a high proliferative rate assessed by Ki67 staining, and that FGFR1 amplification is found in 16-27% of luminal B type breast cancers. Our data suggests that amplification and over-expression of FGFR1 may be a major contributor to poor prognosis in luminal type breast cancers, driving anchorage independent proliferation and endocrine therapy resistance.