Formisano, Luigi (2017) Association of FGFR1 with ER-alpha maintains ligand-independent ER transcription and mediates resistance to estrogen deprivation in ER+ breast cancer. [Tesi di dottorato]

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Item Type:	Tesi di dottorato
Lingua:	English
Title:	Association of FGFR1 with ER-alpha maintains ligand-independent ER transcription and mediates resistance to estrogen deprivation in ER+ breast cancer
Creators:	Creators Email Formisano, Luigi l.formisano84@gmail.com
Date:	10 April 2017
Number of Pages:	48
Institution:	Università degli Studi di Napoli Federico II
Department:	Medicina Clinica e Chirurgia
Dottorato:	Terapie avanzate medico-chirurgiche
Ciclo di dottorato:	29
Coordinatore del Corso di dottorato:	nome email Di Minno, Giovanni diminno@unina.it
Tutor:	nome email De Placido, Sabino UNSPECIFIED Arteaga, Carlos UNSPECIFIED
Date:	10 April 2017
Number of Pages:	48
Uncontrolled Keywords:	breast cancer, FGFR1, endocrine resistance
Settori scientifico-disciplinari del MIUR:	Area 06 - Scienze mediche > MED/06 - Oncologia medica
Date Deposited:	27 Apr 2017 10:10
Last Modified:	14 Mar 2018 11:59
URI:	http://www.fedoa.unina.it/id/eprint/11765
DOI:	10.6093/UNINA/FEDOA/11765

Abstract

In a cohort of patients with ER+ breast cancer, tumors with FGFR1 amplification retained high proliferation upon estrogen deprivation with the aromatase inhibitor letrozole. Estrogen deprivation increased total and nuclear FGFR1 and FGF ligands in ER+/FGFR1-amplified primary tumors and breast cancer cells. In estrogen-free conditions, FGFR1 associated with ER-alpha in tumor cell nuclei and regulated the transcription of ER-dependent genes. This interaction and transcriptional output were inducible by FGF ligands and blocked by a kinase-dead FGFR1 mutant or FGFR kinase inhibitors. ChIP-seq of FGFR1 amplified cells treated with FGF3 showed binding of FGFR1 and ERα to DNA. Treatment with the ER downregulator fulvestrant and/or the FGFR inhibitor lucitanib reduced binding of ERα or FGFR1 to DNA. RNA-seq data from FGFR1-amplified patients’ tumors treated with letrozole showed enrichment of estrogen response and E2F target genes. Finally, growth of ER+/FGFR1-amplified breast cancer cells and patient-derived xenografts was more potently inhibited by fulvestrant and lucitanib combined than each drug alone, suggesting a causal association of aberrant FGFR signaling with endocrine resistance. These data suggest the ER-alpha pathway is still active in estrogen-deprived ER+/FGFR1-amplified breast cancers and, therefore, these tumors should be considered for treatment with a combination of ER and FGFR antagonists.

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