MNK1/NODAL Signaling Promotes Invasive Progression of Breast Ductal Carcinoma In Situ

The mechanisms by which breast cancers progress from relatively indolent ductal carcinoma (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) signali...

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Published in:	Cancer research (Chicago, Ill.) Ill.), 2019-04, Vol.79 (7), p.1646-1657
Main Authors:	Guo, Qianyu, Li, Vivian Z, Nichol, Jessica N, Huang, Fan, Yang, William, Preston, Samuel E J, Talat, Zahra, Lefrère, Hanne, Yu, Henry, Zhang, Guihua, Basik, Mark, Gonçalves, Christophe, Zhan, Yao, Plourde, Dany, Su, Jie, Torres, Jose, Marques, Maud, Habyan, Sara Al, Bijian, Krikor, Amant, Frédéric, Witcher, Michael, Behbod, Fariba, McCaffrey, Luke, Alaoui-Jamali, Moulay, Giannakopoulos, Nadia V, Brackstone, Muriel, Postovit, Lynne-Marie, Del Rincón, Sonia V, Miller, Jr, Wilson H
Format:	Article
Language:	eng
Subjects:	Animals Breast Carcinoma In Situ - metabolism Breast Carcinoma In Situ - pathology Breast Neoplasms - metabolism Breast Neoplasms - pathology Carcinoma, Ductal, Breast - metabolism Carcinoma, Ductal, Breast - pathology Cell Line, Tumor Cell Proliferation CRISPR-Cas Systems Disease Progression Female Heterografts Humans Intracellular Signaling Peptides and Proteins - genetics Intracellular Signaling Peptides and Proteins - metabolism Mice Mice, Nude Nodal Protein - metabolism Protein Serine-Threonine Kinases - genetics Protein Serine-Threonine Kinases - metabolism Signal Transduction
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Summary:	The mechanisms by which breast cancers progress from relatively indolent ductal carcinoma (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 . The MNK1/2 inhibitor SEL201 blocked DCIS progression to invasive disease . 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 to invasive ductal carcinoma.
ISSN:	0008-5472 1538-7445