Transient SNAIL1 expression is necessary for metastatic competence in breast cancer.
Transient SNAIL1 expression is necessary for metastatic competence in breast cancer.
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DOI：
10.1158/0008-5472.can-14-0923
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发表时间：
2014-11-01
期刊：
影响因子：
11.2
通讯作者：
Tran DD
中科院分区：
文献类型：
--
作者：
Tran HD;Luitel K;Kim M;Zhang K;Longmore GD;Tran DD
基于人乳腺肿瘤转录组分析和肿瘤细胞系和异种移植物实验，SNAIL1被认为调控乳腺癌转移。然而，体内遗传学实验支持SNAIL1在免疫肿瘤微环境中发展的乳腺癌转移中的作用尚未确定。为了解决这个问题，我们通过将一个内源性SNAIL1报告基因与一个可诱导的SNAIL1转基因结合，建立了一个SNAIL1遗传模型。通过使用多种乳腺癌遗传模型，我们证明了内源性SNAIL1的表达仅限于最终扩散的原发肿瘤。SNAIL1基因缺失发生在癌前期或原发肿瘤达到可触及的大小后，表明晚期转移是转移的主要驱动因素，并且依赖于SNAIL1。重要的是，SNAIL1在乳腺癌转移过程中的表达是短暂的和强迫短暂的，而不是持续的，SNAIL1在乳腺肿瘤中的表达足以增加转移。
SNAIL1 has been suggested to regulate breast cancer metastasis based on analyses of human breast tumor transcriptomes and experiments using cancer cell lines and xenografts. However, in vivo genetic experimental support for a role for SNAIL1 in breast cancer metastasis that develops in an immunocompetent tumor microenvironment has not been determined. To address this question, we created a genetic SNAIL1 model by coupling an endogenous SNAIL1 reporter with an inducible SNAIL1 transgene. Using multiple genetic models of breast cancer, we demonstrated that endogenous SNAIL1 expression was restricted to primary tumors that ultimately disseminate. SNAIL1 gene deletion either during the premalignant phase or after primary tumors have reached a palpable size blunted metastasis, indicating that late metastasis was the main driver of metastasis and that this was dependent on SNAIL1. Importantly, SNAIL1 expression during breast cancer metastasis was transient and forced transient, but not continuous, SNAIL1 expression in breast tumors was sufficient to increase metastasis.