Nuclear FGFR1 Regulates Gene Transcription and Promotes Antiestrogen Resistance in ER+ Breast Cancer
- Authors
- Servetto, Alberto; Kollipara, Rahul; Formisano, Luigi; Lin, Chang-Ching; Lee, Kyung min; Sudhan, Dhivya R.; Gonzalez-Ericsson, Paula I.; Chatterjee, Sumanta; Guerrero-Zotano, Angel; Mendiratta, Saurabh; Akamatsu, Hiroaki; James, Nicholas; Bianco, Roberto; Hanker, Ariella B.; Kittler, Ralf; Arteaga, Carlos L.
- Issue Date
- Aug-2021
- Publisher
- AMER ASSOC CANCER RESEARCH
- Citation
- CLINICAL CANCER RESEARCH, v.27, no.15, pp.4379 - 4396
- Indexed
- SCIE
SCOPUS
- Journal Title
- CLINICAL CANCER RESEARCH
- Volume
- 27
- Number
- 15
- Start Page
- 4379
- End Page
- 4396
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/190276
- DOI
- 10.1158/1078-0432.CCR-20-3905
- ISSN
- 1078-0432
- Abstract
- 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.,
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