Association of FGFR1 with ERαmaintains ligand-independent ER transcription and mediates resistance to estrogen deprivation in ER+ breast cancer
| Autor: | Valerie M. Jansen, Yao Lu, Stefano Cairo, Thomas Stricker, Carlos L. Arteaga, Luis J. Schwarz, Justin M. Balko, Jennifer M. Giltnane, Angel Guerrero-Zotano, Monica M. Estrada, Roberto Bianco, Neil E. Bhola, Jean Gabriel Judde, Kimberly M. Stauffer, Ingrid A. Mayer, Melinda E. Sanders, Christian D. Young, Luigi Formisano, Olivier Deas, Katherine E. Hutchinson, Teresa C. Dugger |
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| Přispěvatelé: | Formisano, Luigi, Stauffer, Kimberly Mae, Young, Christian D, Bhola, Neil E, Guerrero Zotano, Angel L, Jansen, Valerie M, Estrada, Monica 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, Thoma, Arteaga, Carlos L. |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research medicine.medical_specialty Transcription Genetic medicine.drug_class Cell Breast Neoplasms Biology Tyrosine-kinase inhibitor 03 medical and health sciences Mice 0302 clinical medicine Estrogen Receptor Modulators Internal medicine Cell Line Tumor medicine Animals Humans Molecular Targeted Therapy Receptor Fibroblast Growth Factor Type 1 E2F Protein Kinase Inhibitors Neoplasm Staging Fulvestrant Cell growth Letrozole Estrogen Receptor alpha Gene Amplification Fibroblast Growth Factors Gene Expression Regulation Neoplastic stomatognathic diseases Disease Models Animal Protein Transport FGFR1 breast cancer estrogen resistance 030104 developmental biology Endocrinology medicine.anatomical_structure Oncology Estrogen Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research Female Estrogen receptor alpha medicine.drug Signal Transduction |
| Popis: | Purpose: FGFR1 amplification occurs in approximately 15% of estrogen receptor–positive (ER+) human breast cancers. We investigated mechanisms by which FGFR1 amplification confers antiestrogen resistance to ER+ breast cancer.Experimental Design: ER+ tumors from patients treated with letrozole before surgery were subjected to Ki67 IHC, FGFR1 FISH, and RNA sequencing (RNA-seq). ER+/FGFR1–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.Results: ER+/FGFR1–amplified tumors in patients treated with letrozole maintained cell proliferation (Ki67). Estrogen deprivation increased total and nuclear FGFR1 and FGF ligands expression in ER+/FGFR1–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+/FGFR1–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 FGFR1-amplified patients' tumors treated with letrozole showed enrichment of estrogen response and E2F target genes. Finally, growth of ER+/FGFR1–amplified cells and PDXs was more potently inhibited by fulvestrant and lucitanib combined than each drug alone.Conclusions: These data suggest the ERα pathway remains active in estrogen-deprived ER+/FGFR1–amplified breast cancers. Therefore, these tumors are endocrine resistant and should be candidates for treatment with combinations of ER and FGFR antagonists. Clin Cancer Res; 23(20); 6138–50. ©2017 AACR. |
| Databáze: | OpenAIRE |
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