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 |
|---|---|
| Resource language: | 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 |
| 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 |
Collection description
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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