Thyroid cancer is the most common malignancy of the endocrine organs. In order to further understand the tumorigenesis and progression of papillary thyroid carcinoma (PTC), the present study performed whole transcriptome sequence analysis. It was found that Cbp/p300-interacting transactivators with glutamic acid [E] and aspartic acid [D]-rich C-terminal domain 1 (CITED1) was a novel potential PTC-associated gene in thyroid cancer. The expression level and clinicopathological features of CITED1 were then assessed in The Cancer Genome Atlas (TCGA) database. The expression of CITED1 was knocked down and the biological function of CITED1 in PTC cell lines was examined. The results showed that upregulated CITED1 was associated with lymph node metastasis (P=0.006) and clinical stage (P=0.003). In order to differentiate PTC tissues and normal tissues, an area under the curve was constructed of a receiver operating characteristic of 91.3% for the TCGA cohort and 85.3% for a validated cohort. The downregulated expression of CITED1 significantly inhibited cell proliferation, colony formation, migration and invasion in the PTC cell lines. The present study demonstrated that CITED1 is important in the tumorigenesis and metastasis of PTC and may be a potential therapeutic target in PTC.
Recent studies indicated that genotoxic treatment may promote cancer cell invasion. Moreover, resistance to chemotherapy highly correlates with high metastatic potential in breast cancer patients. Nevertheless, the molecular mechanisms linking chemotherapeutic resistance to metastasis remain poorly understood. Here, we show that microRNA-181a (miR-181a) plays an important role in promoting chemodrug-induced breast cancer metastasis. Treatment with genotoxic drugs increases miR-181a expression in triple-negative breast cancer cells, which is dependent on NF-kB activation by DNA damaging agents. Genotoxic NF-κB activation upregulates IL-6 expression and secretion in breast cancer cells, which leads to STAT3 (signal transducer and activator of transcription 3) phosphorylation and activation. Activated STAT3 translocates onto miR-181a gene promoter region and enhances its transcription in response to genotoxic treatments. Interestingly, chemodrug treatment also induces epigenetic modifications, such as increased histone H3 Ser28 phosphorylation and decreased H3 Lys27 trimethylation, at miR-181a promoter region, which are also required for miR-181a up-regulation. In addition, we found overexpression of miR-181a in breast cancer cells significantly enhanced cell invasion and metastasis, while inhibiting miR-181a reduced cell aggressiveness upon genotoxic exposure. We further show that miR-181a directly suppresses the expression of ataxia telangiectasia mutated (ATM) in breast cancer cells, which plays a pivotal role in DNA damage response and cancer progression. Therefore, our findings support a critical role of DNA damage-induced miR-181a in promoting breast cancer metastasis following chemotherapeutic treatment. Further exploration of molecular mechanisms regulating miR-181a induction and miR-181a-driven aggressive behaviors of breast cancer cells in response to chemotherapy may reveal novel approaches to reduce metastasis and improve therapeutic response in breast cancers by targeting miRNAs. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-08-10.
Background: Human epidermal growth factor receptor 2 (HER2) plays a vital role in breast cancer progression in patients who overexpress HER2, thus promoting the rapid progress of targeted drugs development and therapy strategies advancement targeting this gene. Pyrotinib, approved in clinical by the Chinese State Drug Administration, is a novel pan-ErbB kinase inhibitor and exhibits better efficacy than lapatinib. Alpelisib is a selective PI3K p110α inhibitor approved for application in HR+, HER2-, PIK3CA mutated breast cancers. We assumed that combining pyrotinib with alpelisib worked better than single-drug treatment.Methods: We performed the drug combination assay to evaluate the combination index (CI) of pyrotinib and alpelisib in HER2+ breast cancer cell lines. Cell functional assays, RT-qPCR (Real Time-Quantitative Polymerase Chain Reaction) and western blotting were performed to elucidate the combined efficacy of two drugs and explore the underlying mechanism. Then we established the acquired pyrotinib resistant HER2+ breast cancer cell lines and evaluate the combined efficacy of two drugs in pyrotinib resistant cells and explore the potential mechanisms.Results: Our data exhibited that a combination of alpelisib and pyrotinib showed a synergistic effect in HER2+ breast cancer by enhancing cell proliferation and migration decrease, G0-G1 cell cycle arrest, and apoptosis rate increase. Additionally, alpelisib combined with pyrotinib showed a tremendous synergistic effect in acquired pyrotinib resistant cells.Conclusions: Our results provided the preclinical evidence that a combination of pyrotinib and alpelisib as an effective therapeutic strategy in treating HER2+ breast cancer, whether patients were sensitive or resistant to pyrotinib treatment.
Female breast cancer is the most frequently diagnosed cancer. The long-term survival rates for this disease have increased; however, the unique demand for high-quality healthcare to improve breast-cancer survivorship are commonly unmet. The Mediterranean diet (MD) is associated with reduced breast-cancer risk and various health-related benefits in the general population, but its effect on breast-cancer survivors remains uncertain. The objective of this systematic review and meta-analysis was to assess current evidence from randomised controlled trials (RCTs) and observational studies (cohort, cross-sectional and case-control) regarding the effect of the MD on survival, quality of life (QoL) and health-related outcomes in female breast-cancer survivors. MEDLINE, EMBASE, Web of Science and the Cochrane library were searched for studies published before and including April 2022. Two reviewers independently screened the literature and completed the data extraction and risk-of-bias assessment. Eleven studies (fifteen reports) were included, including two RCTs, four cohort and five cross-sectional studies. The meta-analysis of the cohort studies showed strong evidence of an inverse association between high adherence to the MD and all-cause mortality (hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.66–0.93, I2: 0%, Grading of Recommendations Assessment, Development and Evaluation (GRADE) = low certainty of evidence) and non-breast-cancer mortality (HR 0.67, 95% CI 0.50–0.90, I2: 0%, GRADE = very low certainty of evidence). The associations between high adherence to the MD and QoL and health-related parameters were not consistent. These findings highlight the potential of adherence to the MD to reduce the risk of mortality. Future research with better study designs, as well as more consistent measurements of QoL and MD adherence, taking into account changes in MD adherence over time and population subgroups, is needed to provide more robust evidence on the survival, QoL and health-related outcomes in BC survivors.
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