Association of FGFR1 with ERα Maintains Ligand-Independent ER Transcription and Mediates Resistance to Estrogen Deprivation in ER(+) Breast Cancer.
Association of FGFR1 with ERα Maintains Ligand-Independent ER Transcription and Mediates Resistance to Estrogen Deprivation in ER(+) Breast Cancer.
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DOI：
10.1158/1078-0432.ccr-17-1232
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发表时间：
2017-10-15
期刊：
影响因子：
--
通讯作者：
Arteaga CL
中科院分区：
文献类型：
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作者：
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 T;Arteaga CL
FGFR 1扩增发生在约15%的ER+乳腺癌中，我们研究了FGFR 1扩增赋予ER+乳腺癌抗雌激素抵抗的机制。对手术前接受来曲唑治疗的患者的ER+肿瘤进行Ki 67免疫组织化学、FGFR 1 FISH和RNA测序。用FGFR 1 siRNA或FGFR酪氨酸激酶抑制剂lucitanib处理ER+/FGFR 1扩增的乳腺癌细胞和患者来源的异种移植物（PDX）。终点为细胞/异种移植物生长、通过免疫共沉淀和邻位连接测定的FGFR 1/ERα结合、通过ChIP测序测定的ER基因组活性和通过RT-PCR测定的基因表达。来曲唑治疗患者中ER+/FGFR 1扩增的肿瘤维持细胞增殖（Ki 67）。雌激素剥夺增加ER+/FGFR 1扩增的原发性肿瘤和乳腺癌细胞中总的和核的FGFR 1和FGF配体表达。在无雌激素条件下，FGFR 1与肿瘤细胞核中的ERα结合，并调节ER依赖基因的转录。这种关联被激酶死亡的FGFR 1突变体和lucitanib治疗抑制。雌激素剥夺ER+/FGFR 1扩增细胞的ChIP-seq分析显示FGFR 1和ERα与DNA结合。氟维司群和/或卢西替尼处理降低了FGFR 1和ERα与DNA的结合。来自用来曲唑治疗的FGFR 1扩增患者肿瘤的RNA-seq数据显示雌激素反应和E2 F靶基因的富集。最后，氟维司群和Lucitanib联合使用比单独使用每种药物更有效地抑制ER+/FGFR 1扩增细胞和PDX的生长。这些数据表明，ERα通路在雌激素缺乏的ER+/FGFR 1扩增的乳腺癌中仍然活跃。因此，这些肿瘤是内分泌耐药的，应该是ER和FGFR拮抗剂联合治疗的候选者。
FGFR1 amplification occurs in ~15% of ER+ human breast cancers.We investigated mechanisms by which FGFR1 amplification confers antiestrogen resistance to ER+ breast cancer. ER+ tumors from patients treated with letrozole before surgery were subjected to Ki67 immunohistochemistry, FGFR1 FISH, and RNA-sequencing. ER+/FGFR1 amplified breast cancer cells and patient-derived xenografts (PDXs) were treated with FGFR1 siRNA or the FGFR tyrosine kinase inhibitor lucitanib. Endpoints were cell/xenograft growth, FGFR1/ERα association by co-immunoprecipitation and proximity ligation, ER genomic activity by ChIP-sequencing, and gene expression by RT-PCR. 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. 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.