ERN1 and ALPK1 inhibit differentiation of bi-potential tumor-initiating cells in human breast cancer

• Published in: Oncotarget 2016-12, Vol.7 (50), p.83278-83293
• Main Authors: Strietz, Juliane, Stepputtis, Stella S, Preca, Bogdan-Tiberius, Vannier, Corinne, Kim, Mihee M, Castro, David J, Au, Qingyan, Boerries, Melanie, Busch, Hauke, Aza-Blanc, Pedro, Heynen-Genel, Susanne, Bronsert, Peter, Kuster, Bernhard, Stickeler, Elmar, Brabletz, Thomas, Oshima, Robert G, Maurer, Jochen
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Carbazoles - pharmacology; Caseins - genetics; Caseins - metabolism; Cell Differentiation - drug effects; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Endoribonucleases - antagonists & inhibitors; Endoribonucleases - genetics; Endoribonucleases - metabolism; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Indole Alkaloids - pharmacology; Keratin-5 - genetics; Keratin-5 - metabolism; Mice, Inbred NOD; Mice, SCID; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - enzymology; Neoplastic Stem Cells - pathology; Phenotype; Protein Kinase Inhibitors - pharmacology; Protein Kinases - metabolism; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Research Paper; RNA Interference; Signal Transduction; Time Factors; Transfection; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - enzymology; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - pathology; Tumor Burden
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.13086

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.