Suppression of invasion and metastasis of triple-negative breast cancer lines by pharmacological or genetic inhibition of slug activity.
Suppression of invasion and metastasis of triple-negative breast cancer lines by pharmacological or genetic inhibition of slug activity.
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DOI：
10.1016/j.neo.2014.10.006
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发表时间：
2014-12
期刊：
影响因子：
--
通讯作者：
Calabretta B
中科院分区：
文献类型：
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作者：
Ferrari-Amorotti G;Chiodoni C;Shen F;Cattelani S;Soliera AR;Manzotti G;Grisendi G;Dominici M;Rivasi F;Colombo MP;Fatatis A;Calabretta B
大多数三阴性乳腺癌（TNBC）表现出与上皮间质转化（EMT）相关的基因表达模式，EMT是一种与转移扩散倾向相关的特征。在基底和间充质型TNBC中检测到EMT调节剂Slug的过表达，并且与E-钙粘蛋白表达减少和侵袭性疾病相关。Slug的作用部分取决于其N-末端SNAG阻遏物结构域与染色质修饰蛋白赖氨酸脱甲基酶1（LSD 1）的相互作用;因此，我们研究了反苯环丙胺[也称为反式-2-苯基环丙胺盐酸盐（PCPA）或Parnate]（一种阻断其与Slug相互作用的LSD 1抑制剂）是否抑制TNBC细胞系的迁移、侵袭和转移扩散。我们在这里表明，PCPA治疗诱导E-钙粘蛋白和其他上皮标志物的表达，并显着抑制TNBC细胞系MDA-MB-231和BT-549的迁移和侵袭。这些作用通过Slug或LSD 1沉默进行表型模仿。在两种原位乳腺癌模型中，PCPA治疗减少了局部肿瘤生长和肺转移的数量。在血液循环中直接注射MDA-MB-231细胞的小鼠中，PCPA治疗或Slug沉默显著抑制骨转移，但对肺浸润没有影响。因此，阻断Slug活性可以抑制TNBC的转移性扩散，并且可能特异性抑制归巢/定殖至骨。
Most triple-negative breast cancers (TNBCs) exhibit gene expression patterns associated with epithelial-to-mesenchymal transition (EMT), a feature that correlates with a propensity for metastatic spread. Overexpression of the EMT regulator Slug is detected in basal and mesenchymal-type TNBCs and is associated with reduced E-cadherin expression and aggressive disease. The effects of Slug depend, in part, on the interaction of its N-terminal SNAG repressor domain with the chromatin-modifying protein lysine demethylase 1 (LSD1); thus, we investigated whether tranylcypromine [also known as trans-2-phenylcyclopropylamine hydrochloride (PCPA) or Parnate], an inhibitor of LSD1 that blocks its interaction with Slug, suppresses the migration, invasion, and metastatic spread of TNBC cell lines. We show here that PCPA treatment induces the expression of E-cadherin and other epithelial markers and markedly suppresses migration and invasion of TNBC cell lines MDA-MB-231 and BT-549. These effects were phenocopied by Slug or LSD1 silencing. In two models of orthotopic breast cancer, PCPA treatment reduced local tumor growth and the number of lung metastases. In mice injected directly in the blood circulation with MDA-MB-231 cells, PCPA treatment or Slug silencing markedly inhibited bone metastases but had no effect on lung infiltration. Thus, blocking Slug activity may suppress the metastatic spread of TNBC and, perhaps, specifically inhibit homing/colonization to the bone.