Nuclear FGFR1 regulates gene transcription and promotes antiestrogen resistance in ERþ breast cancer

Alberto Servetto, Rahul Kollipara, Luigi Formisano, Chang Ching Lin, Kyung Min Lee, Dhivya R Sudhan, Paula I. Gonzalez-Ericsson, Sumanta Chatterjee, Angel Guerrero-Zotano, Saurabh Mendiratta, Hiroaki Akamatsu, Nicholas James, Roberto Bianco, Ariella B. Hanker, Ralf Kittler, Carlos L. Arteaga

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Purpose: FGFR1 overexpression has been associated with endocrine resistance in ERþ 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 FGFR1 IHC. MCF7 cells were transduced with FGFR1(SP-)(NLS) to promote nuclear FGFR1 overexpression. FGFR1 genomic activity in ERþ/FGFR1-amplified breast cancer cells ± FOXA1 siRNA or ± the FGFR tyrosine kinase inhibitor (TKI) erdafitinib was examined by chromatin immunoprecipitation sequencing (ChIP-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 ERþ 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 FGFR1 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 ERþ breast cancer. Nuclear FGFR1 activity was unaffected by FGFR TKIs, thus supporting the development of treatment strategies to inhibit nuclear FGFR1 in ERþ/FGFR1 overexpressing breast cancer.

Original languageEnglish (US)
Pages (from-to)4379-4396
Number of pages18
JournalClinical Cancer Research
Volume27
Issue number15
DOIs
StatePublished - Aug 1 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Nuclear FGFR1 regulates gene transcription and promotes antiestrogen resistance in ERþ breast cancer'. Together they form a unique fingerprint.

Cite this