Association of FGFR1 with ERα maintains ligand-independent ER transcription and mediates resistance to estrogen deprivation in ER+ breast cancer

Luigi Formisano, Kimberly M. Stauffer, Christian D. Young, Neil E. Bhola, Angel L. Guerrero-Zotano, Valerie M. Jansen, Monica M. Estrada, Katherine E. Hutchinson, Jennifer M. Giltnane, Luis J. Schwarz, Yao Lu, Justin M. Balko, Olivier Deas, Stefano Cairo, Jean Gabriel Judde, Ingrid A. Mayer, Melinda Sanders, Teresa C. Dugger, Roberto Bianco, Thomas P. StrickerCarlos L. Arteaga

Research output: Contribution to journalArticle

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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/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.

Original languageEnglish (US)
Pages (from-to)6138-6151
Number of pages14
JournalClinical Cancer Research
Volume23
Issue number20
DOIs
StatePublished - Oct 15 2017

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letrozole
Estrogens
Breast Neoplasms
Ligands
RNA Sequence Analysis
Neoplasms
Heterografts
Estrogen Receptor Modulators
DNA
Growth
Cell Nucleus
Protein-Tyrosine Kinases
Small Interfering RNA
Genes
Ligation
Research Design
Phosphotransferases
Therapeutics
Cell Proliferation
Gene Expression

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Association of FGFR1 with ERα maintains ligand-independent ER transcription and mediates resistance to estrogen deprivation in ER+ breast cancer. / Formisano, Luigi; Stauffer, Kimberly M.; 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, Thomas P.; Arteaga, Carlos L.

In: Clinical Cancer Research, Vol. 23, No. 20, 15.10.2017, p. 6138-6151.

Research output: Contribution to journalArticle

Formisano, L, Stauffer, KM, Young, CD, Bhola, NE, Guerrero-Zotano, AL, Jansen, VM, Estrada, MM, Hutchinson, KE, Giltnane, JM, Schwarz, LJ, Lu, Y, Balko, JM, Deas, O, Cairo, S, Judde, JG, Mayer, IA, Sanders, M, Dugger, TC, Bianco, R, Stricker, TP & Arteaga, CL 2017, 'Association of FGFR1 with ERα maintains ligand-independent ER transcription and mediates resistance to estrogen deprivation in ER+ breast cancer', Clinical Cancer Research, vol. 23, no. 20, pp. 6138-6151. https://doi.org/10.1158/1078-0432.CCR-17-1232
Formisano, Luigi ; Stauffer, Kimberly M. ; 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, Thomas P. ; Arteaga, Carlos L. / Association of FGFR1 with ERα maintains ligand-independent ER transcription and mediates resistance to estrogen deprivation in ER+ breast cancer. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 20. pp. 6138-6151.
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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/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.",
author = "Luigi Formisano and Stauffer, {Kimberly M.} and Young, {Christian D.} and Bhola, {Neil E.} and Guerrero-Zotano, {Angel L.} and Jansen, {Valerie M.} and Estrada, {Monica M.} and Hutchinson, {Katherine E.} and Giltnane, {Jennifer M.} and Schwarz, {Luis J.} and Yao Lu and Balko, {Justin M.} and Olivier Deas and Stefano Cairo and Judde, {Jean Gabriel} and Mayer, {Ingrid A.} and Melinda Sanders and Dugger, {Teresa C.} and Roberto Bianco and Stricker, {Thomas P.} and Arteaga, {Carlos L.}",
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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.

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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