ERN1 and ALPK1 inhibit differentiation of bi-potential tumor-initiating cells in human breast cancer
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Juliane Strietz2,*, Stella S. Stepputtis2,3,*, Bogdan-Tiberius Preca2,3,*, Corinne Vannier2,3, Mihee M. Kim1, David J. Castro1, Qingyan Au1, Melanie Boerries3,5, Hauke Busch3,5, Pedro Aza-Blanc1, Susanne Heynen-Genel1, Peter Bronsert8,9,10, Bernhard Kuster6, Elmar Stickeler7, Thomas Brabletz4, Robert G. Oshima1,#, Jochen Maurer1,2,3,#
1Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
2Department of Visceral Surgery, University Hospital Freiburg, German Cancer Consortium (DKTK), Freiburg, Germany
3German Cancer Research Center (DKFZ), Heidelberg, Germany
4Department of Experimental Medicine I, University of Erlangen-Nuernberg, Erlangen, Germany
5Systems Biology of the Cellular Microenvironment at The DKFZ Partner Site Freiburg, German Cancer Consortium (DKTK), Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Freiburg, Germany
6Technische Universitaet Muenchen, Partner Site of the German Cancer Consortium, Freising, Germany
7Department of OBGYN, University Clinic Aachen (UKA), Aachen, Germany
8Department of Surgical Pathology, University Medical Center Freiburg, Freiburg, Germany
9German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
10Institute of Pathology, University Medical Center Freiburg, Freiburg, Germany
*These authors have contributed equally and share first authorship
#These authors have contributed equally and share last authorship
Jochen Maurer, email: [email protected]
Robert G. Oshima, email: [email protected]
Keywords: ALPK1, ERN1, differentiation therapy, human bi-potential tumor-initiating cells, kinase knockdown
Received: March 21, 2016 Accepted: October 21, 2016 Published: November 04, 2016
Cancers are heterogeneous by nature. While traditional oncology screens commonly use a single endpoint of cell viability, altering the phenotype of tumor-initiating cells may reveal alternative targets that regulate cellular growth by processes other than apoptosis or cell division. We evaluated the impact of knocking down expression of 420 kinases in bi-lineage triple-negative breast cancer (TNBC) cells that express characteristics of both myoepithelial and luminal cells. Knockdown of ERN1 or ALPK1 induces bi-lineage MDA-MB-468 cells to lose the myoepithelial marker keratin 5 but not the luminal markers keratin 8 and GATA3. In addition, these cells exhibit increased β-casein production. These changes are associated with decreased proliferation and clonogenicity in spheroid cultures and anchorage-independent growth assays. Confirmation of these assays was completed in vivo, where ERN1- or ALPK1-deficient TNBC cells are less tumorigenic. Finally, treatment with K252a, a kinase inhibitor active on ERN1, similarly impairs anchorage-independent growth of multiple breast cancer cell lines. This study supports the strategy to identify new molecular targets for types of cancer driven by cells that retain some capacity for normal differentiation to a non-tumorigenic phenotype. ERN1 and ALPK1 are potential targets for therapeutic development.
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