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NEDD4 Plays Roles in the Maintenance of Breast Cancer Stem Cell Characteristics.

ABSTRACT: Triple-negative breast cancer (TNBC) is the most aggressive type with poor prognosis among the breast cancers and has a high population of cancer stem cells (CSCs), which are the main target to cure and inhibit TNBC. In this study, we examined the role of neural precursor cell expressed developmentally downregulated protein 4 (NEDD4) in the proliferation, migration, and CSC characteristics of MDA-MB-231, a TNBC cell line. Interestingly, the Kaplan-Meier plotter showed that the survival rate of patients with a higher expression level of NEDD4 was significantly shorter than those of patients with a lower expression only in relatively aggressive and higher stage (grade 3) breast cancer patients. The knockdown of NEDD4 drastically decreased the proliferation, migration, and mammosphere formation in MDA-MB-231 cells. A proteomic analysis revealed the alteration of CSC-related proteins; notably, Myc targets stem cell-like signatures in siNEDD4-treated MDA-MB-231. An immunoassay also showed that the expression and the activity of breast CSC markers are decreased in NEDD4-deleted MDA-MB-231. Taken together, these results indicate that NEDD4 is involved in the maintenance of populations and characteristics of breast CSCs.

SUBMITTER: Jeon SA

PROVIDER: S-EPMC7509455 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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NEDD4 Plays Roles in the Maintenance of Breast Cancer Stem Cell Characteristics.

Jeon Seon-Ae SA Kim Dong Wook DW Lee Da-Bin DB Cho Je-Yoel JY

Frontiers in oncology 20200902

Triple-negative breast cancer (TNBC) is the most aggressive type with poor prognosis among the breast cancers and has a high population of cancer stem cells (CSCs), which are the main target to cure and inhibit TNBC. In this study, we examined the role of neural precursor cell expressed developmentally downregulated protein 4 (NEDD4) in the proliferation, migration, and CSC characteristics of MDA-MB-231, a TNBC cell line. Interestingly, the Kaplan-Meier plotter showed that the survival rate of p ...[more]

PMID: 33014839

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Project description:Background: Cancer stem cells are presumed to have virtually unlimited proliferative and self-renewal abilities and to be highly resistant to chemotherapy, a feature that is associated with overexpression of ATP-binding cassette transporters. We investigated whether prolonged continuous selection of cells for drug resistance enriches cultures for cancer stem-like cells. Methods: Cancer stem cells were defined as CD44+/CD24– cells that could self-renew (ie, generate cells with the tumorigenic CD44+/CD24– phenotype), differentiate, invade, and form tumors in vivo. We used doxorubicin-selected MCF-7/ADR cells, weakly tumorigenic parental MCF-7 cells, and MCF-7/MDR, an MCF-7 subline with forced expression of ABCB1 protein. Cells were examined for cell surface markers and side-population fractions by microarray and flow cytometry, with in vitro invasion assays, and for ability to form mammospheres. Xenograft tumors were generated in mice to examine tumorigenicity (n = 52). The mRNA expression of multidrug resistance genes was examined in putative cancer stem cells and pathway analysis of statistically significantly differentially expressed genes was performed. All statistical tests were two-sided. Results: Pathway analysis showed that MCF-7/ADR cells express mRNAs from ABCB1 and other genes also found in breast cancer stem cells (eg, CD44, TGFB1, and SNAI1). MCF-7/ADR cells were highly invasive, formed mammospheres, and were tumorigenic in mice. In contrast to parental MCF-7 cells, more than 30% of MCF-7/ADR cells had a CD44+/CD24– phenotype, could self-renew, and differentiate (ie, produce CD44+/CD24– and CD44+/CD24+ cells), and overexpressed various multidrug resistance-linked genes (including ABCB1, CCNE1, and MMP9). MCF-7/ADR cells were statistically significantly more invasive in Matrigel than parental MCF-7 cells (MCF-7 cells = 0.82 cell per field and MCF-7/ADR = 7.51 cells per field, difference = 6.69 cells per field, 95% confidence interval = 4.82 to 8.55 cells per field, P<.001). No enrichment in the CD44+/CD24– or CD133+ population was detected in MCF-7/MDR. Conclusion: The cell population with cancer stem cell characteristics increased after prolonged continuous selection for doxorubicin resistance. PARALLEL study design with 4 samples Parental MCF-7 cell line versus Doxorubicin Resistant MCF-7 cell sublines Biological replicates: 2 parental controls, 2 drug resistant, independently grown and harvested. agent:Selection agent is multi-step doxorubicin selection: MCF7226ng, MCF7262ng biological replicate: MCF71, MCF72 biological replicate: MCF226ng, MCF7262ng

Project description:BackgroundCancer stem cells are presumed to have virtually unlimited proliferative and self-renewal abilities and to be highly resistant to chemotherapy, a feature that is associated with overexpression of ATP-binding cassette transporters. We investigated whether prolonged continuous selection of cells for drug resistance enriches cultures for cancer stem-like cells.MethodsCancer stem cells were defined as CD44+/CD24? cells that could self-renew (ie, generate cells with the tumorigenic CD44+/CD24? phenotype), differentiate, invade, and form tumors in vivo. We used doxorubicin-selected MCF-7/ADR cells, weakly tumorigenic parental MCF-7 cells, and MCF-7/MDR, an MCF-7 subline with forced expression of ABCB1 protein. Cells were examined for cell surface markers and side-population fractions by microarray and flow cytometry, with in vitro invasion assays, and for ability to form mammospheres. Xenograft tumors were generated in mice to examine tumorigenicity (n = 52). The mRNA expression of multidrug resistance genes was examined in putative cancer stem cells and pathway analysis of statistically significantly differentially expressed genes was performed. All statistical tests were two-sided.ResultsPathway analysis showed that MCF-7/ADR cells express mRNAs from ABCB1 and other genes also found in breast cancer stem cells (eg, CD44, TGFB1, and SNAI1). MCF-7/ADR cells were highly invasive, formed mammospheres, and were tumorigenic in mice. In contrast to parental MCF-7 cells, more than 30% of MCF-7/ADR cells had a CD44+/CD24? phenotype, could self-renew, and differentiate (ie, produce CD44+/CD24? and CD44+/CD24+ cells) and overexpressed various multidrug resistance-linked genes (including ABCB1, CCNE1, and MMP9). MCF-7/ADR cells were statistically significantly more invasive in Matrigel than parental MCF-7 cells (MCF-7 cells = 0.82 cell per field and MCF-7/ADR = 7.51 cells per field, difference = 6.69 cells per field, 95% confidence interval = 4.82 to 8.55 cells per field, P < .001). No enrichment in the CD44+/CD24? or CD133+ population was detected in MCF-7/MDR.ConclusionThe cell population with cancer stem cell characteristics increased after prolonged continuous selection for doxorubicin resistance.

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NEDD4 Plays Roles in the Maintenance of Breast Cancer Stem Cell Characteristics.

Publications

NEDD4 Plays Roles in the Maintenance of Breast Cancer Stem Cell Characteristics.

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