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Cancer Res. 2019 Jan 18. doi: 10.1158/0008-5472.CAN-18-1602. [Epub ahead of print]

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

Author information

1
Division of Experimental Medicine, McGill University, Montréal, Québec, Canada.
2
Department of Oncology, Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada.
3
Department of Oncology, Katholieke Universiteit Leuven, Leuven, Belgium.
4
Cancer Research Institute of Northern Alberta, Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
5
Goodman Cancer Centre, McGill University, Montréal, Québec, Canada.
6
Department of Pathology and Laboratory Medicine, University of Kansas Medical Centre, Kansas City, Kansas.
7
Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
8
Departments of Surgery and Oncology, Western University, London, Ontario, Canada.
9
Division of Experimental Medicine, McGill University, Montréal, Québec, Canada. wmiller@ldi.jgh.mcgill.ca sonia.delrincon@mcgill.ca.
10
Rossy Cancer Network, McGill University, Montréal, Québec, Canada.

Abstract

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.

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