MNK1/NODAL Signaling Promotes Invasive Progression of Breast Ductal Carcinoma In Situ
MNK1/NODAL Signaling Promotes Invasive Progression of Breast Ductal Carcinoma In Situ
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DOI：
10.1158/0008-5472.can-18-1602
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发表时间：
2019-04-01
期刊：
影响因子：
11.2
通讯作者：
Miller, Wilson H., Jr.
中科院分区：
文献类型：
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作者：
Guo, Qianyu;Li, Vivian Z.;Miller, Wilson H., Jr.
乳腺癌从相对惰性导管原位癌(DCIS)发展到浸润性导管癌(IDC)的机制尚不清楚。然而，这一过程对于获得转移潜能是至关重要的。MAPK相互作用的丝氨酸/苏氨酸蛋白激酶1(MNK1)信号通路可促进细胞侵袭。NODAL是胚胎发育所必需的一种形态原，在乳腺癌中经常重新表达。在这里，我们描述了一个促进DCIS向IDC发展的MNK1/Node信号轴。我们建立了MNK1基因敲除(KO)或成分活性MNK1(CaMNK1)表达的人MCF-10A来源的DCIS细胞系，并将其原位注射到小鼠的乳腺中。MNK1的缺失抑制了结节的表达，抑制了DCIS向IDC的转化，减少了肿瘤的复发和转移。相反，caMNK1诱导结节表达，促进IDC的表达。MNK1/Node轴在体外促进了肿瘤干细胞的特性和侵袭。MNK1/2抑制剂SEL201在体内阻止了DCIS向侵袭性疾病的进展。在临床标本中，微侵袭的IDC和DCIS与低级别(无侵袭)的DCIS相比，表达更高水平的磷酸化MNK1和结节DCIS。总而言之，我们的数据支持进一步开发MNK1抑制剂作为预防浸润性疾病的治疗方法。意义：这些发现为导管癌的进展提供了新的机制见解，并支持临床应用MNK1抑制剂来延缓惰性导管原位癌向浸润性导管癌的进展。
The mechanisms by which breast cancers progress from relatively indolent ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) are not well understood. However, this process is critical to the acquisition of metastatic potential. MAPK-interacting serine/threonine-protein kinase 1 (MNK1) signaling can promote cell invasion. NODAL, a morphogen essential for embryogenic patterning, is often reexpressed in breast cancer. Here we describe a MNK1/NODAL signaling axis that promotes DCIS progression to IDC. We generated MNK1 knockout (KO) or constitutively active MNK1 (caMNK1)-expressing human MCF-10A-derived DCIS cell lines, which were orthotopically injected into the mammary glands of mice. Loss of MNK1 repressed NODAL expression, inhibited DCIS to IDC conversion, and decreased tumor relapse and metastasis. Conversely, caMNK1 induced NODAL expression and promoted IDC. The MNK1/NODAL axis promoted cancer stem cell properties and invasion in vitro. The MNK1/2 inhibitor SEL201 blocked DCIS progression to invasive disease in vivo. In clinical samples, IDC and DCIS with microinvasion expressed higher levels of phospho-MNK1 and NODAL versus low-grade (invasion-free) DCIS. Cumulatively, our data support further development of MNK1 inhibitors as therapeutics for preventing invasive disease.Significance: These findings provide new mechanistic insight into progression of ductal carcinoma and support clinical application of MNK1 inhibitors to delay progression of indolent ductal carcinoma in situ to invasive ductal carcinoma.