MicroRNA-454 may function as an oncogene via targeting AKT in triple negative breast cancer.
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ABSTRACT:
SUBMITTER: Li Q
PROVIDER: S-EPMC5541748 | biostudies-other | 2017 Dec
REPOSITORIES: biostudies-other
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Project description:MicroRNA-454 (miR-454) has been reported to play an oncogenic or tumor suppressor role in most cancers. However, the clinical relevance of miR-454 in breast cancer remains unclear. We examined the expression of miR-454 in a tissue microarray containing 534 breast cancer specimens from female patients at Fudan University Shanghai Cancer Center using in situ hybridization (ISH). Of these, 250 patients formed the training set and the other 284 were the validation set. The relationship between miR-454 and clinical outcome was analyzed by the Kaplan-Meier method. High expression of miR-454 indicated worse disease-free survival (DFS) in both cohorts (P = 0.006 for training set; P = 0.010 for validation set). Furthermore, in the triple-negative breast cancer (TNBC) subtype, miR-454 was positively correlated with worse clinical outcome (P = 0.013 for training set, P = 0.014 for validation set). In addition, patients in the low miR-454 expression cohort had better response to anthracycline compared to non-anthracycline chemotherapy (P = 0.056), but this difference was not observed in the high miR-454 expression cohort. Our findings indicated that miR-454 is a potential predictor of prognosis and chemotherapy response in TNBC.
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Project description:Background: Metastatic triple negative breast cancer (mTNBC) is a heterogeneous disease with poor prognosis. Molecular evolution of TNBC through chemotherapy selection pressure is well recognized but poorly understood. PI3K/AKT/mTOR is one of the most commonly identified oncogenic-driver pathways in breast cancer. The current study is designed to understand the genomic and transcriptomic changes, focusing on the PI3K/AKT/mTOR pathway alterations in paired primary and metastatic TNBCs. Results: Genomic analysis of 7 paired specimens identified 67 known mutations including those from the following signaling pathways: cell cycle, p53, PI3K/AKT/mTOR, RAS/MAPK, and RTK/GF. Principle coordinate analysis (PCoA) identified 4 distinctive molecular groups based on the gene expression patterns of PI3K/AKT/mTOR pathway. Key differentially-expressed genes included AKT3, GSK3B, GNA11, PI3KR1, and GNAQ. Importantly, AKT-targeted therapy showed efficacy in a patient-derived xenograft (PDX) model of TNBC in vivo. Conclusion: Genomic discordance of paired primary and metastatic TNBCs was identified, with significant increase in tumor proliferation pathways seen in metastases. Among the differentially expressed genes, AKT3 can potentially serve as a target for novel combination therapy for treatment of metastatic TNBC. Methods: Paired specimens from 10 patients with TNBCs were identified through an IRB-approved protocol (2002-2015). FoundationOneTM sequencing was performed for genomic profiling, and Affymetrix Human Genechip 2.0st was used for mRNA expression profiling. The similarity among samples was calculated based on Pearson correlation coefficients, which were used to construct hierarchical clustering and heat maps.
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Project description:Upregulation of a disintegrin and metalloprotease 9 (ADAM9) is correlated with progression of cancers, such as prostate, bladder, and pancreatic cancers. However, its role in triple-negative breast cancer (TNBC) is still unclear. Our study aimed to investigate whether ADAM9 is upregulated and promoted the aggressiveness in TNBC. Breast cancer cell lines and patient specimens were used to evaluate the ADAM9 expression by western blotting and immunohistochemistry staining, respectively. Compared with the non-TNBC, ADAM9 expression was significantly increased in TNBC cells and TNBC patient specimens. Based on the data acquired from public databases, the correlation between ADAM9 expression and breast cancer patient survival was analyzed by Kaplan-Meier method. It was shown that ADAM9 overexpression was significantly correlated with poorer survival in patients with TNBC. Furthermore, ADAM9 in TNBC cells was knocked down by small interference RNA and then studied by the MTT/colony formation assay, wound healing assay and transwell invasion assay on the cell proliferation, migration, and invasion, respectively. We found that inhibiting ADAM9 expression suppressed TNBC cell proliferation, migration, and invasion by lowering the activation of AKT/NF-κB pathway. Our results demonstrated that ADAM9 is an important molecule in mediating TNBC aggressiveness and may be a potential useful therapeutic target in TNBC treatment.
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Project description:Circular RNAs (CircRNAs) have attracted increasing attention in the diagnosis and treatment of human cancers. CircUBAP2 has been identified to promote the progression of triple-negative breast cancer (TNBC), but the function of circUBAP2 in the cisplatin (DDP) resistance of TNBC remains obscure. Our investigation showed that circUBAP2 was significantly upregulated in DDP-resistant TNBC and TNBC sensitivity to DDP could be enhanced by silencing of circUBAP2. Moreover, circUBAP2 was revealed to be a ceRNA for miR-300 to upregulate the expression of anti-silencing function 1B histone chaperone (ASF1B). The effect of circUBAP2/miR-300/ASF1B axis on DDP resistance of TNBC was evaluated by rescue experiments, which demonstrated that circUBAP2 inhibited TNBC sensitivity to DDP through miR-300/ASF1B axis. Furthermore, it was discovered that ASF1B activated PI3K/AKT/mTOR signaling to facilitate the DDP resistance of TNBC cells. In summary, this research revealed a novel regulatory mechanism that circUBAP2 functioned as ceRNA of miR-300 to upregulate ASF1B, which further triggered the PI3K/AKT/mTOR (PAM) signaling to enhance the DDP resistance of TNBC.
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Project description:AbstractDel-1 has been linked to the pathogenesis of various cancers, including breast cancer. However, the regulation of Del-1 expression remains unclear. We previously reported the interaction between microRNA-137 (miR-137) and the Del-1 gene. In this study, we investigated miR-496 and miR-137 as regulators of Del-1 expression in triple negative breast cancer (TNBC). Del-1 mRNA and miR-496 were measured by quantitative PCR in breast cancer cells (MDA-MB-231, MCF7, SK-BR3, and T-47D) and tissues from 30 patients with TNBC. The effects of miR-496 on cell proliferation, migration, and invasion were determined with MTT, wound healing, and Matrigel transwell assays, respectively. In MDA-MB-231 cells, miR-496 levels were remarkably low and Del-1 mRNA levels were higher than in other breast cancer cell lines. Luciferase reporter assays revealed that miR-496 binds the 3'-UTR of Del-1 and Del-1 expression is downregulated by miR-496 mimics. Furthermore, miR-496 inhibited the proliferation, migration, and invasion of MDA-MB-231 cells. The effects of miR-496 on cell proliferation were additive with those of miR-137, another miRNA that regulates Del-1 expression. Moreover, in the 30 TNBC specimens, miR-496 was downregulated (P < .005) and the levels of Del-1 in the plasma were significantly elevated as compared with in normal controls (P = .0142). The Cancer Genome Atlas (TCGA) data showed the correlation of miR-496 expression with better overall survival in patients with early TNBC. In in silico and in vitro analyses, we showed that Del-1 is a target of miR-496 in TNBC and thereby affects cancer progression. Our findings suggest that miR-496 and miR-137 additively target Del-1 and act as modulating factors in TNBC. They are potentially new biomarkers for patients with TNBC.
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Project description:As the most malignant subtype of breast cancers, triple-negative breast cancer (TNBC) lacks effective targeted therapeutics clinically to date. In this study, one lead compound FZU-0025-065 with isochromanoindolenine scaffold was identified by a cell-based screening. Among nine breast cancer cell lines tested, TNBC are the most sensitive cell lines to FZU-0025-065. FZU-0025-065 inhibits TNBC cell growth in a time- and dosage-dependent manner. FZU-0025-065 suppresses the expression of cell cycle dependent kinase 4 (CDK4), Cyclin D1 and Cyclin B1; meanwhile, elevates the expression of cell cycle dependent kinase inhibitor p21 and p27. Importantly, we found that FZU-0025-065 suppresses AKT activation in a time- and dosage-dependent manner. Over-expression of constitutive active AKT partially rescues FZU-0025-065 induced cell growth inhibition in MDA-MB-468 cells, indicating FZU-0025-065 suppresses TNBC cell growth partially via inhibiting AKT activation. Finally, FZU-0025-065 suppresses TNBC cell growth in a xenograft mouse model. Taken together, our findings suggested that isochromanoindolenine derivative FZU-0025-065 inhibits TNBC via suppressing the AKT signaling and that FZU-0025-065 may be useful for TNBC treatment.
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