ERN1 and ALPK1 inhibit differentiation of bi-potential tumor-initiating cells in human breast cancer.
Oncotarget
; 7(50): 83278-83293, 2016 Dec 13.
Article
em En
| MEDLINE
| ID: mdl-27829216
ABSTRACT
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 ß-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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Quinases
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Células-Tronco Neoplásicas
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Diferenciação Celular
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Proteínas Serina-Treonina Quinases
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Endorribonucleases
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Neoplasias de Mama Triplo Negativas
Tipo de estudo:
Prognostic_studies
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article