Nuclear FGFR1 Regulates Gene Transcription and Promotes Antiestrogen Resistance in ER+ Breast Cancer

Purpose FGFRI overexpression has been associated with endocrine resistance in ER+ breast cancer. We found FGFR1 localized in the nucleus of breast cancer cells in primary tumors resistant to estrogen suppression. We investigated a role of nuclear FGFR1 on gene transcription and antiestrogen resistance. Experimental Design: Tumors from patients treated with letrozole were subjected to Ki67 and FGFRI IHC. MCF7 cells were transduced with FGFR1(SP-)(NLS) to promote nudear FGFR1 overexpression. FGFR1 genomic activity in ER+/FGFR1-amplified breast cancer cells +/- FOXA1 siRN A or +/- the FGFR tyrosine kinase inhibitor (TKI) erdafitinib was examined by chromatin immunoprecipitation sequencing (Chi P-seq) and RNA sequencing (RNA-seq). The nuclear and chromatin-bound FGFR1 interactome was investigated by mass spectrometry (MS). Results: High nuclear FGFR1 expression in ER+ primary tumors positively correlated with post-letrozole Ki67 values. Nuclear FGFR1 overexpression influenced gene transcription and promoted resistance to estrogen suppression and to fulvestrant in vivo. A gene expression signature induced by nuclear FGFR1 correlated with shorter survival in the METABRIC cohort of patients treated with antiestrogens. ChIP-Seq revealed FGFR1 occupancy at transcription start sites, overlapping with active transcription histone marks. MS analysis of the nuclear FGFRI interactome identified phosphorylated RNA-Polymerase II and FOXA1, with FOXA1 RNAi impairing FGFR1 recruitment to chromatin. Treatment with erdafitinib did not impair nuclear FGFR1 translocation and genomic activity. Conclusions: These data suggest nuclear FGFR1 contributes to endocrine resistance by modulating gene transcription in ER+ breast cancer. Nudear FGFR1 activity was unaffected by FGFR TKIs, thus supporting the development of treatment strategies to inhibit nuclear FGFRI in ER+/FGFRI overexpressing breast cancer.

Automated summary

FGFR1 overexpression in the nucleus of breast cancer cells is associated with endocrine resistance in ER+ breast cancer. Nuclear FGFR1 influences gene transcription and promotes resistance to estrogen suppression and fulvestrant. Treatment with FGFR tyrosine kinase inhibitors does not affect nuclear FGFR1 activity, supporting the development of strategies to inhibit nuclear FGFR1 in ER+/FGFR1 overexpressing breast cancer.