TY - JOUR
T1 - Association of FGFR1 with ERα maintains ligand-independent ER transcription and mediates resistance to estrogen deprivation in ER+ breast cancer
AU - Formisano, Luigi
AU - Stauffer, Kimberly M.
AU - Young, Christian D.
AU - Bhola, Neil E.
AU - Guerrero-Zotano, Angel L.
AU - Jansen, Valerie M.
AU - Estrada, Monica M.
AU - Hutchinson, Katherine E.
AU - Giltnane, Jennifer M.
AU - Schwarz, Luis J.
AU - Lu, Yao
AU - Balko, Justin M.
AU - Deas, Olivier
AU - Cairo, Stefano
AU - Judde, Jean Gabriel
AU - Mayer, Ingrid A.
AU - Sanders, Melinda
AU - Dugger, Teresa C.
AU - Bianco, Roberto
AU - Stricker, Thomas P.
AU - Arteaga, Carlos L.
N1 - Publisher Copyright:
©2017 AACR.
PY - 2017/10/15
Y1 - 2017/10/15
N2 - 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/ERa 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.
AB - 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/ERa 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.
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U2 - 10.1158/1078-0432.CCR-17-1232
DO - 10.1158/1078-0432.CCR-17-1232
M3 - Article
C2 - 28751448
AN - SCOPUS:85031704459
SN - 1078-0432
VL - 23
SP - 6138
EP - 6151
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 20
ER -