journal contribution
posted on 2024-03-06, 15:20 authored by Qianyu Guo, Vivian Z. Li, Jessica N. Nichol, Fan Huang, William Yang, Samuel E.J. Preston, Zahra Talat, Hanne Lefrère, Henry Yu, Guihua Zhang, Mark Basik, Christophe Gonçalves, Yao Zhan, Dany Plourde, Jie Su, Jose Torres, Maud Marques, Sara Al Habyan, Krikor Bijian, Frédéric Amant, Michael Witcher, Fariba Behbod, Luke McCaffrey, Moulay Alaoui-Jamali, Nadia V. Giannakopoulos, Muriel Brackstone, Lynne-Marie Postovit, Sonia V. del Rincón, Wilson H. Miller Supplementary Data from MNK1/NODAL Signaling Promotes Invasive Progression of Breast Ductal Carcinoma In Situ
Funding
Cancer Research Society (CRS)
Gouvernement du Canada | Canadian Institutes of Health Research (CIHR)
Canadian Cancer Society (Société canadienne du cancer)
Rossy Cancer Network
Israel Cancer Research Fund (ICRF)
History
ARTICLE 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.
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.
