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Association of FGFR1 with ERα Maintains Ligand-Independent ER Transcription and Mediates Resistance to Estrogen Deprivation in ER + Breast Cancer

Formisano, Luigi ; Stauffer, Kimberly M ; Young, Christian D ; Bhola, Neil E ; Guerrero-Zotano, Angel L ; Jansen, Valerie M ; Estrada, Mónica M ; Hutchinson, Katherine E ; Giltnane, Jennifer M ; Schwarz, Luis J ; Lu, Yao ; Balko, Justin M ; Deas, Olivier ; Cairo, Stefano ; Judde, Jean-Gabriel ; Mayer, Ingrid A ; Sanders, Melinda ; Dugger, Teresa C ; Bianco, Roberto ; Stricker, Thomas ; Arteaga, Carlos L

Clinical cancer research, 2017-10, Vol.23 (20), p.6138-6150 [Peer Reviewed Journal]

United States: American Association for Cancer Research Inc

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Title:
Association of FGFR1 with ERα Maintains Ligand-Independent ER Transcription and Mediates Resistance to Estrogen Deprivation in ER + Breast Cancer
Author: Formisano, Luigi ; Stauffer, Kimberly M ; Young, Christian D ; Bhola, Neil E ; Guerrero-Zotano, Angel L ; Jansen, Valerie M ; Estrada, Mónica M ; Hutchinson, Katherine E ; Giltnane, Jennifer M ; Schwarz, Luis J ; Lu, Yao ; Balko, Justin M ; Deas, Olivier ; Cairo, Stefano ; Judde, Jean-Gabriel ; Mayer, Ingrid A ; Sanders, Melinda ; Dugger, Teresa C ; Bianco, Roberto ; Stricker, Thomas ; Arteaga, Carlos L
Subjects: Amplification ; Animals ; Antagonists ; Binding ; Breast cancer ; Breast Neoplasms - drug therapy ; Breast Neoplasms - genetics ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Cancer ; Cell Line, Tumor ; Cell proliferation ; Deoxyribonucleic acid ; Deprivation ; Disease Models, Animal ; DNA ; Drug Resistance, Neoplasm - genetics ; E2F protein ; Estrogen Receptor alpha - antagonists & inhibitors ; Estrogen Receptor alpha - genetics ; Estrogen Receptor alpha - metabolism ; Estrogen Receptor Modulators - pharmacology ; Estrogen receptors ; Estrogens ; Experimental design ; Female ; Fibroblast growth factor ; Fibroblast growth factor receptor 1 ; Fibroblast growth factor receptors ; Fibroblast Growth Factors - genetics ; Fibroblast Growth Factors - metabolism ; Fulvestrant ; Gene Amplification ; Gene expression ; Gene Expression Regulation, Neoplastic ; Gene sequencing ; Genes ; Humans ; Inhibition ; Kinases ; Ligands ; Mice ; Molecular Targeted Therapy ; Neoplasm Staging ; Nuclei ; Nuclei (cytology) ; Patients ; Polymerase chain reaction ; Protein Kinase Inhibitors - pharmacology ; Protein Transport ; Protein-tyrosine kinase ; Receptor, Fibroblast Growth Factor, Type 1 - antagonists & inhibitors ; Receptor, Fibroblast Growth Factor, Type 1 - genetics ; Receptor, Fibroblast Growth Factor, Type 1 - metabolism ; Ribonucleic acid ; RNA ; Signal Transduction - drug effects ; siRNA ; Surgery ; Transcription ; Transcription, Genetic ; Tumors ; Tyrosine ; Xenografts
Is Part Of: Clinical cancer research, 2017-10, Vol.23 (20), p.6138-6150
Notes: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Description: amplification occurs in approximately 15% of estrogen receptor-positive (ER ) human breast cancers. We investigated mechanisms by which amplification confers antiestrogen resistance to ER breast cancer. ER tumors from patients treated with letrozole before surgery were subjected to Ki67 IHC, FGFR1 FISH, and RNA sequencing (RNA-seq). ER / -amplified breast cancer cells, and patient-derived xenografts (PDX) were treated with FGFR1 siRNA or the FGFR tyrosine kinase inhibitor lucitanib. Endpoints were cell/xenograft growth, FGFR1/ERα association by coimmunoprecipitation and proximity ligation, ER genomic activity by ChIP sequencing, and gene expression by RT-PCR. ER / -amplified tumors in patients treated with letrozole maintained cell proliferation (Ki67). Estrogen deprivation increased total and nuclear FGFR1 and FGF ligands expression in ER / amplified primary tumors and breast cancer cells. In estrogen-free conditions, FGFR1 associated with ERα in tumor cell nuclei and regulated the transcription of ER-dependent genes. This association was inhibited by a kinase-dead FGFR1 mutant and by treatment with lucitanib. ChIP-seq analysis of estrogen-deprived ER / -amplified cells showed binding of FGFR1 and ERα to DNA. Treatment with fulvestrant and/or lucitanib reduced FGFR1 and ERα binding to DNA. RNA-seq data from -amplified patients' tumors treated with letrozole showed enrichment of estrogen response and E2F target genes. Finally, growth of ER / amplified cells and PDXs was more potently inhibited by fulvestrant and lucitanib combined than each drug alone. s These data suggest the ERα pathway remains active in estrogen-deprived ER / -amplified breast cancers. Therefore, these tumors are endocrine resistant and should be candidates for treatment with combinations of ER and FGFR antagonists. .
Publisher: United States: American Association for Cancer Research Inc
Language: English

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Association of FGFR1 with ERα Maintains Ligand-Independent ER Transcription and Mediates Resistance to Estrogen Deprivation in ER + Breast Cancer

United States: American Association for Cancer Research Inc

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