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


ABSTRACT: 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/ER? 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 ER? 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 ER? to DNA. Treatment with fulvestrant and/or lucitanib reduced FGFR1 and ER? 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 ER? 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.

SUBMITTER: Formisano L 

PROVIDER: S-EPMC6681458 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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

Formisano Luigi L   Stauffer Kimberly M KM   Young Christian D CD   Bhola Neil E NE   Guerrero-Zotano Angel L AL   Jansen Valerie M VM   Estrada Mónica M MM   Hutchinson Katherine E KE   Giltnane Jennifer M JM   Schwarz Luis J LJ   Lu Yao Y   Balko Justin M JM   Deas Olivier O   Cairo Stefano S   Judde Jean-Gabriel JG   Mayer Ingrid A IA   Sanders Melinda M   Dugger Teresa C TC   Bianco Roberto R   Stricker Thomas T   Arteaga Carlos L CL  

Clinical cancer research : an official journal of the American Association for Cancer Research 20170727 20


<b>Purpose:</b><i>FGFR1</i> amplification occurs in approximately 15% of estrogen receptor-positive (ER<sup>+</sup>) human breast cancers. We investigated mechanisms by which <i>FGFR1</i> amplification confers antiestrogen resistance to ER<sup>+</sup> breast cancer.<b>Experimental Design:</b> ER<sup>+</sup> tumors from patients treated with letrozole before surgery were subjected to Ki67 IHC, FGFR1 FISH, and RNA sequencing (RNA-seq). ER<sup>+</sup>/<i>FGFR1</i>-amplified breast cancer cells, and  ...[more]

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