Functional and prognostic significance of the genomic amplification of frizzled 6 (FZD6) in breast cancer.
Functional and prognostic significance of the genomic amplification of frizzled 6 (FZD6) in breast cancer.
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乳腺癌中毛躁6（FZD6）基因组扩增的功能和预后意义。
DOI：
10.1002/path.4841
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发表时间：
2017-02
期刊：
影响因子：
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通讯作者：
Sala A
中科院分区：
文献类型：
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作者：
Corda G;Sala G;Lattanzio R;Iezzi M;Sallese M;Fragassi G;Lamolinara A;Mirza H;Barcaroli D;Ermler S;Silva E;Yasaei H;Newbold RF;Vagnarelli P;Mottolese M;Natali PG;Perracchio L;Quist J;Grigoriadis A;Marra P;Tutt AN;Piantelli M;Iacobelli S;De Laurenzi V;Sala A
卷曲受体介导Wnt配体信号传导，其在调节组织发育和分化中至关重要，并且通常在癌症中失调。在这项研究中，我们发现编码Wnt受体frizzled 6（FZD 6）的基因在乳腺癌中经常扩增，在三阴性乳腺癌（TNBC）亚型中的发病率增加。在乳腺癌细胞系中消除FZD 6表达：（1）抑制运动和侵袭;（2）诱导类器官三维培养物的形状更对称;（3）抑制体内骨和肝转移。从机制上讲，FZD 6信号传导是纤连蛋白基质组装所必需的，干扰肌动蛋白细胞骨架的组织。在FZD 6耗尽的三阴性MDA-MB-231细胞中异位递送纤连蛋白重排肌动蛋白细胞骨架并恢复表皮生长因子介导的侵袭。在局部淋巴结阴性（早期）乳腺癌患者中，肿瘤细胞FZD 6蛋白阳性可确定患者的远端无复发生存率降低。多变量分析表明，FZD 6表达在TNBC肿瘤中具有独立的预后意义，可预测远处而非局部复发。我们的结论是，在我们的研究中确定的FZD 6-纤连蛋白肌动蛋白轴可以用于药物开发的高度转移形式的乳腺癌，如TNBC。© 2016作者。病理学杂志由John Wiley & Sons Ltd代表大不列颠和爱尔兰病理学会出版。
Frizzled receptors mediate Wnt ligand signalling, which is crucially involved in regulating tissue development and differentiation, and is often deregulated in cancer. In this study, we found that the gene encoding the Wnt receptor frizzled 6 (FZD6) is frequently amplified in breast cancer, with an increased incidence in the triple‐negative breast cancer (TNBC) subtype. Ablation of FZD6 expression in mammary cancer cell lines: (1) inhibited motility and invasion; (2) induced a more symmetrical shape of organoid three‐dimensional cultures; and (3) inhibited bone and liver metastasis in vivo. Mechanistically, FZD6 signalling is required for the assembly of the fibronectin matrix, interfering with the organization of the actin cytoskeleton. Ectopic delivery of fibronectin in FZD6‐depleted, triple‐negative MDA‐MB‐231 cells rearranged the actin cytoskeleton and restored epidermal growth factor‐mediated invasion. In patients with localized, lymph node‐negative (early) breast cancer, positivity of tumour cells for FZD6 protein identified patients with reduced distant relapse‐free survival. Multivariate analysis indicated an independent prognostic significance of FZD6 expression in TNBC tumours, predicting distant, but not local, relapse. We conclude that the FZD6–fibronectin actin axis identified in our study could be exploited for drug development in highly metastatic forms of breast cancer, such as TNBC. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.