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Isoliquiritigenin Derivative Regulates miR-374a/BAX Axis to Suppress Triple-Negative Breast Cancer Tumorigenesis and Development.

ABSTRACT: Triple-negative breast cancer (TNBC) is a subtype of breast cancer that accounts for the largest proportion of breast cancer-related deaths. Thus, it is imperative to search for novel drug candidates with potent anti-TNBC effects. Recent studies suggest that isoliquiritigenin (ISL) can significantly suppress the growth, migration, and invasion of breast cancer cells. We previously synthesized ISL derivatives and found that 3',4',5',4?-tetramethoxychalcone (TMC) inhibits TNBC cell proliferation to a greater degree than ISL. The present study aimed to investigate the mechanisms underlying the anti-TNBC effects of TMC in vitro and in vivo. We show that TMC significantly inhibits the proliferative, migratory, and invasive abilities of MDA-MB-231 and BT549 cells. TMC induces apoptosis through the upregulation of Bax and downregulation of Bcl-2. PCR arrays demonstrate a significant decrease in miR-374a expression in TNBC cells after 24-h TMC treatment. MiR-374a is overexpressed in TNBC cells and has oncogenic properties. Real-time PCR analysis confirmed that TMC inhibits miR-374a in a dose-dependent manner, and luciferase assays confirmed that BAX is targeted by miR-374a. Further, we show that TMC increases Bax protein and mRNA levels by inhibiting miR-374a. TMC also attenuates TNBC tumor volumes and weights in vivo. These results demonstrate that TMC inhibits TNBC cell proliferation, foci formation, migration, invasion, and tumorigenesis, suggesting its potential to serve as a novel drug for treating TNBC through miR-374a repression.

SUBMITTER: Peng F

PROVIDER: S-EPMC7137655 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Isoliquiritigenin Derivative Regulates miR-374a/BAX Axis to Suppress Triple-Negative Breast Cancer Tumorigenesis and Development.

Peng Fu F Xiong Liang L Xie Xiaofang X Tang Hailin H Huang Ruizhen R Peng Cheng C

Frontiers in pharmacology 20200331

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that accounts for the largest proportion of breast cancer-related deaths. Thus, it is imperative to search for novel drug candidates with potent anti-TNBC effects. Recent studies suggest that isoliquiritigenin (ISL) can significantly suppress the growth, migration, and invasion of breast cancer cells. We previously synthesized ISL derivatives and found that 3',4',5',4″-tetramethoxychalcone (TMC) inhibits TNBC cell proliferation t ...[more]

PMID: 32296334

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Project description:PurposeTriple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer that is frequently treated with chemotherapy. However, many patients exhibit either de novo chemoresistance or ultimately develop resistance to chemotherapy, leading to significantly high mortality rates. Therefore, increasing the efficacy of chemotherapy has potential to improve patient outcomes.MethodsHere, we performed whole transcriptome sequencing (both RNA and small RNA-sequencing), coupled with network simulations and patient survival data analyses to build a novel miRNA-mRNA interaction network governing chemoresistance in TNBC. We performed cell proliferation assay, Western blotting, RNAi/miRNA mimic experiments, FN coating, 3D cultures, and ChIP assays to validate the interactions in the network, and their functional roles in chemoresistance. We developed xenograft models to test the therapeutic potential of the identified key miRNA/proteins in potentiating chemoresponse in vivo. We also analyzed several patient datasets to evaluate the clinical relevance of our findings.ResultsWe identified fibronectin (FN1) as a central chemoresistance driver gene. Overexpressing miR-326 reversed FN1-driven chemoresistance by targeting FN1 receptor, ITGA5. miR-326 was downregulated by increased hypoxia/HIF1A and ECM stiffness in chemoresistant tumors, leading to upregulation of ITGA5 and activation of the downstream FAK/Src signaling pathways. Overexpression of miR-326 or inhibition of ITGA5 overcame FN1-driven chemotherapy resistance in vitro by inhibiting FAK/Src pathway and potentiated the efficacy of chemotherapy in vivo. Importantly, lower expression of miR-326 or higher levels of predicted miR-326 target genes was significantly associated with worse overall survival in chemotherapy-treated TNBC patients.ConclusionFN1 is central in chemoresistance. In chemoresistant tumors, hypoxia and resulting ECM stiffness repress the expression of the tumor suppressor miRNA, miR-326. Hence, re-expression of miR-326 or inhibition of its target ITGA5 reverses FN1-driven chemoresistance making them attractive therapeutic approaches to enhance chemotherapy response in TNBCs.

Dataset Information

Isoliquiritigenin Derivative Regulates miR-374a/BAX Axis to Suppress Triple-Negative Breast Cancer Tumorigenesis and Development.

Publications

Isoliquiritigenin Derivative Regulates miR-374a/BAX Axis to Suppress Triple-Negative Breast Cancer Tumorigenesis and Development.

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