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

Fu Peng,Hailin Tang,Liang Xiong,Ruizhen Huang,Xiaofang Xie,Cheng Peng

doi:10.3389/fphar.2020.00378

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.

Highlights

Breast cancer is the cancer most commonly diagnosed in females worldwide (Siegel et al, 2018), and part of its devastating impact is due to the existence of triple-negative breast cancer (TNBC) (Choi et al, 2019)
The results suggested that TMC (> 5 mM) significantly inhibited Triple-negative breast cancer (TNBC) cell proliferation after treatment for 24 and 48 h (p < 0.01)
Our study identified that TMC significantly inhibited miR-374a in TNBC cells, and upregulation of miR-374a partially reversed its effects on Bax mRNA and protein expression, indicating that TMC as a potent inhibitor of miR-374a in TNBC cells

Summary

Introduction

Breast cancer is the cancer most commonly diagnosed in females worldwide (Siegel et al, 2018), and part of its devastating impact is due to the existence of triple-negative breast cancer (TNBC) (Choi et al, 2019). Compared to other cancer subtypes, current targeted or endocrine therapies cannot treat TNBC, leading to its incidence being disproportionally associated with breast cancer-related deaths (Bianchini et al, 2016). The oncogenic abilities of miR-374a were first reported in non-small cell lung cancer (NSCLC), where it promoted cell migration and invasion (Miko et al, 2009; Wang et al, 2014). MiR-374a promotes cell growth in gastric cancer through its direct interaction with SRCIN1 (Xu et al, 2015). MiR-374a increases the percentage of migratory and invasive breast cancer cells and promotes metastasis through the Wnt and Akt pathways (Cai et al, 2013). MiR374a knockdown inhibits breast cancer cell proliferation, colony formation, migration, and invasion (Zhang et al, 2018). Additional studies indicate that miR-374a is upregulated in TNBC patients, and high expression of miR-374a promotes TNBC development (Son et al, 2019)

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Discussion

Conclusion