Servetto, Alberto (2021) Nuclear FGFR1 regulates gene transcription and promotes antiestrogen resistance in ER+ breast cancer. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Lingua: English
Title: Nuclear FGFR1 regulates gene transcription and promotes antiestrogen resistance in ER+ breast cancer
Creators:
CreatorsEmail
Servetto, Albertoalberto.servetto@unina.it
Date: 12 February 2021
Number of Pages: 71
Institution: Università degli Studi di Napoli Federico II
Department: Medicina Clinica e Chirurgia
Dottorato: Terapie avanzate biomediche e chirurgiche
Ciclo di dottorato: 33
Coordinatore del Corso di dottorato:
nomeemail
Di Minno, Giovannigiovanni.diminno@unina.it
Tutor:
nomeemail
Bianco, RobertoUNSPECIFIED
Date: 12 February 2021
Number of Pages: 71
Uncontrolled Keywords: FGFR1; Breast Cancer
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/06 - Oncologia medica
Additional Information: alternative email address: albeservetto@gmail.com
Date Deposited: 24 Feb 2021 09:48
Last Modified: 07 Jun 2023 10:30
URI: http://www.fedoa.unina.it/id/eprint/13976

Abstract

FGFR1 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. 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 ER+/FGFR1-amplified breast cancer cells ± FOXA1 siRNA or ± the FGFR tyrosine kinase inhibitor (TKI) erdafitinib was examined by ChIP-Seq and RNA-Seq. The nuclear and chromatin-bound FGFR1 interactome was investigated by Mass Spectrometry (MS). 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 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. These data suggest nuclear FGFR1 contributes to endocrine resistance by modulating gene transcription in ER+ breast cancer. Nuclear FGFR1 activity was unaffected by FGFR TKIs, thus supporting the development of treatment strategies to inhibit nuclear FGFR1 in ER+/FGFR1 overexpressing breast cancer.

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