Integrative Bioinformatics Study Reveals Tangeretin Targets and Molecular Mechanisms Against Metastatic Breast Cancer

Abstract Background: Agents that target metastasis are important to improve treatment efficacy in patients with breast cancer. Tangeretin, a citrus flavonoid, exhibits antimetastatic effects on breast cancer cells, but its molecular mechanism remains unclear.Results: Tangeretin targets were retrieved from PubChem, whereas metastatic breast cancer regulatory genes were downloaded from PubMed. In total, 58 genes were identified as potential therapeutic target genes of tangeretin (PTs). Gene ontology analysis with Webgestalt showed that the PTs participate in the biological process of stimulus response, are the cellular components of the nucleus and the membrane, and play molecular roles in enzyme regulation. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that the PTs regulate the PI3K/Akt pathway. Genetic alterations for each target gene were MTOR (3%), NOTCH1 (4%), TP53 (42%), MMP9 (4%), NFKB1 (3%), PIK3CA (32%), PTGS2 (15%), and RELA (5%). The Kaplan–Meier plot displayed that patients with low mRNA expression levels of MTOR, TP53, MMP9, NFKB1, PTGS2, and RELA and high expression of PIK3CA had a significantly better prognosis than their counterparts. Further validation of gene expression by using GEPIA revealed that the mRNA expression of MMP9 was significantly lower in breast cancer tissues than in normal tissues, whereas the mRNA expression of PTGS2 showed the opposite. Analysis with ONCOMINE demonstrated that the mRNA expression levels of MMP9 and NFKB1 were significantly higher in metastatic breast cancer cells than in normal tissues. The results of molecular docking analyses revealed the advantage of tangeretin as an inhibitor of PIK3CA, MMP9, PTGS2, and IKK.Conclusion: Tangeretin inhibits metastasis in breast cancer cells by targeting TP53, PTGS2, MMP9, and PIK3CA and regulating the PI3K/Akt signaling pathway. Further investigation is needed to validate the results of this study.

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Integrative Bioinformatics Study of Tangeretin Potential Targets for Preventing Metastatic Breast Cancer

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/2234554 ◽

2021 ◽

Vol 2021 ◽

pp. 1-15

Author(s):

Adam Hermawan ◽

Herwandhani Putri ◽

Naufa Hanif ◽

Muthi Ikawati

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Mrna Expression ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Metastatic Breast ◽

Genetic Alterations ◽

Pathway Enrichment ◽

Normal Tissues ◽

Kaplan Meier

Agents that target metastasis are important to improve treatment efficacy in patients with breast cancer. Tangeretin, a citrus flavonoid, exhibits antimetastatic effects on breast cancer cells, but its molecular mechanism remains unclear. Tangeretin targets were retrieved from PubChem, whereas metastatic breast cancer regulatory genes were downloaded from PubMed. In total, 58 genes were identified as potential therapeutic target genes of tangeretin (PTs). GO and KEGG pathway enrichment analyses of PTs were performed using WebGestalt (WEB-based Gene SeT AnaLysis Toolkit). The PPI network was analyzed using STRING-DB v11.0 and visualized by Cytoscape software. Hub genes were selected on the basis of the highest degree score as calculated by the CytoHubba plugin. Genetic alterations of the PTs were analyzed using cBioPortal. The prognostic values of the PTs were evaluated with the Kaplan–Meier plot. The expression of PTs across breast cancer samples was confirmed using GEPIA. The reliability of the PTs in metastatic breast cancer cells was validated using ONCOMINE. Molecular docking was performed to foresee the binding sites of tangeretin with PIK3Cα, MMP9, PTGS2, COX-2, and IKK. GO analysis showed that PTs participate in the biological process of stimulus response, are the cellular components of the nucleus and the membrane, and play molecular roles in enzyme regulation. KEGG pathway enrichment analysis revealed that PTs regulate the PI3K/Akt pathway. Genetic alterations for each target gene were MTOR (3%), NOTCH1 (4%), TP53 (42%), MMP9 (4%), NFKB1 (3%), PIK3CA (32%), PTGS2 (15%), and RELA (5%). The Kaplan–Meier plot showed that patients with low mRNA expression levels of MTOR, TP53, MMP9, NFKB1, PTGS2, and RELA and high expression of PIK3CA had a significantly better prognosis than their counterparts. Further validation of gene expression by using GEPIA revealed that the mRNA expression of MMP9 was significantly higher in breast cancer tissues than in normal tissues, whereas the mRNA expression of PTGS2 showed the opposite. Analysis with ONCOMINE demonstrated that the mRNA expression levels of MMP9 and NFKB1 were significantly higher in metastatic breast cancer cells than in normal tissues. The results of molecular docking analyses revealed the advantage of tangeretin as an inhibitor of PIK3CA, MMP9, PTGS2, and IKK. Tangeretin inhibits metastasis in breast cancer cells by targeting TP53, PTGS2, MMP9, and PIK3CA and regulating the PI3K/Akt signaling pathway. Further investigation is needed to validate the results of this study.

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Breast Cancer Cells Response to the Antineoplastic Agents Cisplatin, Carboplatin, and Doxorubicin at the mRNA Expression Levels of Distinct Apoptosis-Related Genes, Including the New Member, BCL2L12

Annals of the New York Academy of Sciences ◽

10.1196/annals.1397.005 ◽

2007 ◽

Vol 1095 (1) ◽

pp. 35-44 ◽

Cited By ~ 26

Author(s):

H. THOMADAKI ◽

A. SCORILAS

Keyword(s):

Breast Cancer ◽

Mrna Expression ◽

Cancer Cells ◽

Antineoplastic Agents ◽

Breast Cancer Cells ◽

Expression Levels ◽

Mrna Expression Levels

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Widespread Alternative Splicing Changes in Metastatic Breast Cancer Cells

Cells ◽

10.3390/cells10040858 ◽

2021 ◽

Vol 10 (4) ◽

pp. 858

Author(s):

Jagyeong Oh ◽

Davide Pradella ◽

Changwei Shao ◽

Hairi Li ◽

Namjeong Choi ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Alternative Splicing ◽

Cancer Cells ◽

Cancer Patients ◽

Cancer Progression ◽

Breast Cancer Cells ◽

Metastatic Breast ◽

Breast Cancer Patients ◽

Expression Levels

Aberrant alternative splicing (AS) is a hallmark of cancer and a potential target for novel anti-cancer therapeutics. Breast cancer-associated AS events are known to be linked to disease progression, metastasis, and survival of breast cancer patients. To identify altered AS programs occurring in metastatic breast cancer, we perform a global analysis of AS events by using RNA-mediated oligonucleotide annealing, selection, and ligation coupled with next-generation sequencing (RASL-seq). We demonstrate that, relative to low-metastatic, high-metastatic breast cancer cells show different AS choices in genes related to cancer progression. Supporting a global reshape of cancer-related splicing profiles in metastatic breast cancer we found an enrichment of RNA-binding motifs recognized by several splicing regulators, which have aberrant expression levels or activity during breast cancer progression, including SRSF1. Among SRSF1-regulated targets we found DCUN1D5, a gene for which skipping of exon 4 in its pre-mRNA introduces a premature termination codon (PTC), thus generating an unstable transcript degraded by nonsense-mediated mRNA decay (NMD). Significantly, distinct breast cancer subtypes show different DCUN1D5 isoform ratios with metastatic breast cancer expressing the highest level of the NMD-insensitive DCUN1D5 mRNA, thus showing high DCUN1D5 expression levels, which are ultimately associated with poor overall and relapse-free survival in breast cancer patients. Collectively, our results reveal global AS features of metastatic breast tumors, which open new possibilities for the treatment of these aggressive tumor types.

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