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 - Funding Information:
This study was funded by NIH Breast SPORE grant P50 CA098131, Vanderbilt-Ingram Cancer Center Support grant P30 CA68485, Susan G. Komen for the Cure Foundation grant SAC100013 (to C.L. Arteaga), and a grant from the Breast Cancer Research Foundation (to C.L. Arteaga). J.M. Balko was supported by NIH/NCI4R00 CA181491 grant and Susan G. Komen Career Catalyst Research award CCR 299052. V.M. Jansen was supported by Conquer Cancer Foundation ASCO Young Investigator Award 8364 and Susan G. Komen Postdoctoral Fellowship Grant PDF15329319. T.P. Stricker was supported by NIH grant K08 CA148912.
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 -