KLF6-SV1 drives breast cancer metastasis and is associated with poor survival.
KLF6-SV1 drives breast cancer metastasis and is associated with poor survival.
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DOI：
10.1126/scitranslmed.3004688
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发表时间：
2013-01-23
影响因子：
17.1
通讯作者：
Narla G
中科院分区：
文献类型：
--
作者：
Hatami R;Sieuwerts AM;Izadmehr S;Yao Z;Qiao RF;Papa L;Look MP;Smid M;Ohlssen J;Levine AC;Germain D;Burstein D;Kirschenbaum A;DiFeo A;Foekens JA;Narla G
转移是癌症死亡的主要原因。对驱动这一复杂多步骤过程的机制的更透彻理解将有助于识别和表征疾病进展的治疗靶向遗传驱动因素。我们证明，KLF 6-SV 1，KLF 6肿瘤抑制基因的致癌剪接变异体，与671例淋巴结阴性乳腺癌患者的转移潜能增加和生存率低相关。KLF 6-SV 1在乳腺上皮细胞系中的过表达导致上皮细胞向间充质细胞样转变，并在多种体内模型中驱动侵袭性多器官转移性疾病。此外，KLF 6-SV 1功能丧失研究证明了上皮和侵袭性较小表型的逆转。结合起来，这些发现暗示KLF 6-SV 1是乳腺癌转移的关键驱动因素，可以区分惰性和致命的早期疾病，并为浸润性乳腺癌提供潜在的治疗靶点。
Metastasis is the major cause of cancer mortality. A more thorough understanding of the mechanisms driving this complex multistep process will aid in the identification and characterization of therapeutically targetable genetic drivers of disease progression. We demonstrate that KLF6-SV1, an oncogenic splice variant of the KLF6 tumor suppressor gene, is associated with increased metastatic potential and poor survival in a cohort of 671 lymph node–negative breast cancer patients. KLF6-SV1 overexpression in mammary epithelial cell lines resulted in an epithelial-to-mesenchymal–like transition and drove aggressive multiorgan metastatic disease in multiple in vivo models. Additionally, KLF6-SV1 loss-of-function studies demonstrated reversion to an epithelial and less invasive phenotype. Combined, these findings implicate KLF6-SV1 as a key driver of breast cancer metastasis that distinguishes between indolent and lethal early-stage disease and provides a potential therapeutic target for invasive breast cancer.