Andrographolide Suppresses the Growth and Metastasis of Luminal-Like Breast Cancer by Inhibiting the NF-κB/miR-21-5p/PDCD4 Signaling Pathway.

Junchen Li,Jianwei Dai,Lingyun Zheng,Cuiling Qi,Zinan He,Lixun Huang,Qian-Qian Zhang,Minggui Chen,Youfa Duan,Jiangchao Li,Li Zixuan,Xiaoming Li,Yi Ding,Rongxin Zhang,Yuying Yao,Lijing Wang

doi:10.3389/fcell.2021.643525

Abstract

Tumor growth and metastasis are responsible for breast cancer-related mortality. Andrographolide (Andro) is a traditional anti-inflammatory drug used in the clinic that inhibits NF-κB activation. Recently, Andro has been found in the treatment of various cancers. Andro inhibits breast cell proliferation and invasion and induces apoptosis via activating various signaling pathways. Therefore, the underlying mechanisms with regard to the antitumor effects of Andro still need to be further confirmed. Herein, a MMTV-PyMT spontaneous luminal-like breast cancer lung metastatic transgenic tumor model was employed to estimate the antitumor effects of Andro on breast cancer in vivo. Andro significantly inhibited tumor growth and metastasis in MMTV-PyMT mice and suppressed the cell proliferation, migration, and invasion of MCF-7 breast cancer cells in vitro. Meanwhile, Andro significantly inhibited the expression of NF-κB, and the downregulated NF-κB reduced miR-21-5p expression. In addition, miR-21-5p dramatically inhibited the target gene expression of programmed cell death protein 4 (PDCD4). In the current study, we demonstrated the potential anticancer effects of Andro on luminal-like breast cancer and indicated that Andro inhibits the expression of miR-21-5p and further promotes PDCD4 via NF-κB suppression. Therefore, Andro could be an antitumor agent for the treatment of luminal-like breast cancer in the clinic.

Highlights

Breast cancer is the most common malignant tumor among women with a rising incidence rate
All the results indicated that Andro could significantly inhibit the cell proliferation of MCF-7 luminal-like breast cancer cells in a dose- and time-dependent manner
Andro-induced programmed cell death 4 (PDCD4) expression in MCF7 was abolished by miR-21-5p mimic treatment (Figure 6F). These results indicate that Andro inactivates NF-κB signaling to inhibit the expression of miR-21-5p, and the inhibition of miR-21-5p stimulates PDCD4 expression to inhibit luminal-like breast cancer growth, metastasis, and invasion

Summary

Introduction

Breast cancer is the most common malignant tumor among women with a rising incidence rate. It is one of the important causes of female deaths worldwide (Siegel et al, 2020). Luminal A and B breast cancers accounted for 37.1 and 8.6%, respectively, of patients with distant metastasis (Ihemelandu et al, 2008). Lumi-like breast cancer has a relatively high mortality rate due to distal metastasis. There is no effective target therapy to treat metastatic luminal-like breast cancer. The expression of NF-κB is highly correlated with the occurrence, late development, and metastasis of breast cancer (Yamamoto et al, 2013). Whether NF-κB could be an effective therapeutic target in metastatic luminal-like breast cancer still needs to be further investigated

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