A novel lung metastasis signature links Wnt signaling with cancer cell self-renewal and epithelial-mesenchymal transition in basal-like breast cancer.
A novel lung metastasis signature links Wnt signaling with cancer cell self-renewal and epithelial-mesenchymal transition in basal-like breast cancer.
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一种新型的肺转移特征将Wnt信号传导与癌细胞自我更新和上皮 - 间质转变联系起来。
DOI：
10.1158/0008-5472.can-08-4135
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发表时间：
2009-07-01
期刊：
影响因子：
11.2
通讯作者：
Kuperwasser C
中科院分区：
文献类型：
--
作者：
DiMeo TA;Anderson K;Phadke P;Fan C;Perou CM;Naber S;Kuperwasser C
转移的建立取决于癌细胞获得迁移表型的能力以及它们在远处组织中重建继发性肿瘤的能力。在上皮癌中，例如乳腺癌，上皮-间质转化（EMT）与基底样乳腺癌相关，产生具有干细胞样性质的细胞，并使癌细胞扩散和转移成为可能。然而，将干细胞样特征与EMT联系起来的分子机制尚未确定。利用人乳腺癌肺转移的原位模型，我们发现了一个预后不良的基因特征，其中wnt信号通路的几个组分在早期肺转移中过表达。在这个标签中发现的wnt基因与人类基底细胞样乳腺癌密切相关。我们发现，通过LRP 6抑制wnt信号传导降低了癌细胞自我更新和体内接种肿瘤的能力。此外，wnt信号的抑制导致乳腺上皮分化标志物的重新表达和EMT转录因子SLUG和TWIST的抑制。总的来说，这些结果提供了基底样乳腺癌自我更新，EMT和转移之间的分子联系。
The establishment of metastasis depends on the ability of cancer cells to acquire a migratory phenotype combined with their capacity to recreate a secondary tumor in a distant tissue. In epithelial cancers, such as those of the breast, the epithelial-mesenchymal transition (EMT) is associated with basal-like breast cancers, generates cells with stem-like properties, and enables cancer cell dissemination and metastasis. However, the molecular mechanism(s) that connects stem cell–like characteristics with EMT has yet to be defined. Using an orthotopic model of human breast cancer metastasis to lung, we identified a poor prognosis gene signature, in which several components of the wnt signaling pathway were overexpressed in early lung metastases. The wnt genes identified in this signature were strongly associated with human basal-like breast cancers. We found that inhibiting wnt signaling through LRP6 reduced the capacity of cancer cells to self-renew and seed tumors in vivo. Furthermore, inhibition of wnt signaling resulted in the reexpression of breast epithelial differentiation markers and repression of EMT transcription factors SLUG and TWIST. Collectively, these results provide a molecular link between self-renewal, EMT, and metastasis in basal-like breast cancers.