Fibroblast growth factor receptor 4 (FGFR4) and fibroblast growth factor 19 (FGF19) autocrine enhance breast cancer cells survival.
Fibroblast growth factor receptor 4 (FGFR4) and fibroblast growth factor 19 (FGF19) autocrine enhance breast cancer cells survival.
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DOI：
10.18632/oncotarget.9328
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发表时间：
2016-09-06
期刊：
影响因子：
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通讯作者：
Leong CO
中科院分区：
文献类型：
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作者：
Tiong KH;Tan BS;Choo HL;Chung FF;Hii LW;Tan SH;Khor NT;Wong SF;See SJ;Tan YF;Rosli R;Cheong SK;Leong CO
基底样乳腺癌是一种侵袭性肿瘤亚型，预后较差。发现介导肿瘤细胞存活的潜在机制，以及开发针对这些途径的新型药物，是基底样乳腺癌患者的优先事项。通过功能性筛选确定基底样乳腺癌细胞生长的关键驱动因素，我们确定成纤维细胞生长因子受体4 （FGFR4）是细胞存活的潜在介质。我们发现FGFR4主要通过激活PI3K/AKT介导癌细胞存活。重要的是，基底样乳腺癌细胞的一个亚群也分泌成纤维细胞生长因子19 (FGF19)，这是FGFR4特异性的典型配体。sirna介导的FGF19沉默或通过抗FGF19抗体（1A6）中和细胞外FGF19可降低AKT磷酸化，抑制癌细胞生长，仅在FGFR4+/FGF19+乳腺癌细胞中增强阿霉素敏感性。同样，在287例原发性乳腺肿瘤中，有82例（28.6%）也观察到FGFR4/FGF19共表达，它们的表达与AKT磷酸化、Ki-67染色、更高的肿瘤分期和基底样表型密切相关。总之，我们的研究结果证明了FGFR4/FGF19自分泌信号通路的存在，该信号通路介导基底样乳腺癌细胞亚群的存活，并提示该自分泌环的失活可能潜在地作为未来乳腺癌治疗的一种新的治疗干预手段。
Basal-like breast cancer is an aggressive tumor subtype with poor prognosis. The discovery of underlying mechanisms mediating tumor cell survival, and the development of novel agents to target these pathways, is a priority for patients with basal-like breast cancer. From a functional screen to identify key drivers of basal-like breast cancer cell growth, we identified fibroblast growth factor receptor 4 (FGFR4) as a potential mediator of cell survival. We found that FGFR4 mediates cancer cell survival predominantly via activation of PI3K/AKT. Importantly, a subset of basal-like breast cancer cells also secrete fibroblast growth factor 19 (FGF19), a canonical ligand specific for FGFR4. siRNA-mediated silencing of FGF19 or neutralization of extracellular FGF19 by anti-FGF19 antibody (1A6) decreases AKT phosphorylation, suppresses cancer cell growth and enhances doxorubicin sensitivity only in the FGFR4+/FGF19+ breast cancer cells. Consistently, FGFR4/FGF19 co-expression was also observed in 82 out of 287 (28.6%) primary breast tumors, and their expression is strongly associated with AKT phosphorylation, Ki-67 staining, higher tumor stage and basal-like phenotype. In summary, our results demonstrated the presence of an FGFR4/FGF19 autocrine signaling that mediates the survival of a subset of basal-like breast cancer cells and suggest that inactivation of this autocrine loop may potentially serve as a novel therapeutic intervention for future treatment of breast cancers.