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]
| Tipologia del documento: |
Tesi di dottorato
|
| Lingua: |
English |
| Titolo: |
Association of FGFR1 with ER-alpha maintains ligand-independent ER transcription and mediates resistance to estrogen deprivation in ER+ breast cancer |
| Autori: |
| Autore | Email |
|---|
| Formisano, Luigi | l.formisano84@gmail.com |
|
| Data: |
10 Aprile 2017 |
| Numero di pagine: |
48 |
| Istituzione: |
Università degli Studi di Napoli Federico II |
| Dipartimento: |
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 | [non definito] | | Arteaga, Carlos | [non definito] |
|
| Data: |
10 Aprile 2017 |
| Numero di pagine: |
48 |
| Parole chiave: |
breast cancer, FGFR1, endocrine resistance |
| Settori scientifico-disciplinari del MIUR: |
Area 06 - Scienze mediche > MED/06 - Oncologia medica |
[error in script]
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| Depositato il: |
27 Apr 2017 10:10 |
| Ultima modifica: |
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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