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

Autor:	Formisano L; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.; Department of Clinical Medicine, University of Naples Federico II, Naples, Italy., Stauffer KM; Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, Tennessee., Young CD; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee., Bhola NE; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee., Guerrero-Zotano AL; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee., Jansen VM; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee., Estrada MM; Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee., Hutchinson KE; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee., Giltnane JM; Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, Tennessee., Schwarz LJ; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee., Lu Y; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee., Balko JM; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.; Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.; Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee., Deas O; XenTech, Evry, France., Cairo S; XenTech, Evry, France.; LTTA Center, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy., Judde JG; XenTech, Evry, France., Mayer IA; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.; Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee., Sanders M; Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.; Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee., Dugger TC; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee., Bianco R; Department of Clinical Medicine, University of Naples Federico II, Naples, Italy., Stricker T; Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, Tennessee. carlos.arteaga@vanderbilt.edu thomas.stricker@vanderbilt.edu.; Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee., Arteaga CL; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. carlos.arteaga@vanderbilt.edu thomas.stricker@vanderbilt.edu.; Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.; Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2017 Oct 15; Vol. 23 (20), pp. 6138-6150. Date of Electronic Publication: 2017 Jul 27.
DOI:	10.1158/1078-0432.CCR-17-1232
Abstrakt:	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. Conclusion s : 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 . (©2017 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu