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Identifying the Effect of Ursolic Acid Against Triple-Negative Breast Cancer: Coupling Network Pharmacology With
Yubao Zhang1, Xiaoran Ma2, Huayao Li3
1School of Basic Medicine, Qingdao University, Qingdao, China.
Abstract:
Triple negative breast cancer (TNBC) is a subtype of breast cancer with complex heterogeneity, high invasiveness, and long-term poor prognosis. With the development of molecular pathology and molecular genetics, the gene map of TNBC with distinctive biological characteristics has been outlined more clearly. Natural plant extracts such as paclitaxel, vinblastine, colchicine etc., have occupied an important position in the treatment of hormone-independent breast cancer. Ursolic acid (UA), a triterpenoid acid compound derived from apple, pear, loquat leaves, etc., has been reported to be effective in a variety of cancer treatments, but there are few reports on the treatment of TNBC. This study performed comprehensive bioinformatics analysis and in vitro experiments to identify the effect of UA on TNBC treatment and its potential molecular mechanism. Our results showed that UA could not only reduce the proliferation, migration, and invasion in MDA-MB-231 and MDA-MB-468 cell lines with a dose-dependent manner but also induce cell cycle arrest and apoptosis. Meanwhile, we collected the gene expression data GSE45827 and GSE65194 from GEO for comparison between TNBC and normal cell type and obtained 724 DEGs. Subsequently, PLK1 and CCNB1 related to TNBC were screened as the key targets via topological analysis and molecular docking, and gene set enrichment analysis identified the key pathway as the p53 signaling pathway. In addition, quantitative real-time PCR and western blot verified the key genes were PLK1 and CCNB1. In vivo and in vitro experiments showed that UA could inhibit the growth of TNBC cells, and down-regulate the protein expression levels of PLK1 and CCNB1 by mediating p53 signaling pathway. These findings provide strong evidence for UA intervention in TNBC via multi-target therapy.
Insights
Ursolic acid (UA) effectively inhibits triple-negative breast cancer (TNBC) by reducing cell growth and inducing apoptosis. It targets PLK1 and CCNB1 via the p53 signaling pathway, offering a potential multi-target therapy for TNBC.
Area of Science:
- Oncology
- Molecular Biology
- Bioinformatics
Background:
- Triple-negative breast cancer (TNBC) presents significant therapeutic challenges due to its heterogeneity and poor prognosis.
- Natural compounds are explored for cancer treatment, with Ursolic acid (UA) showing promise in various cancers but limited study in TNBC.
Purpose of the Study:
- To investigate the efficacy of Ursolic acid (UA) in treating triple-negative breast cancer (TNBC).
- To elucidate the molecular mechanisms underlying UA's anti-TNBC effects using bioinformatics and experimental approaches.
Main Methods:
- Comprehensive bioinformatics analysis of gene expression data (GSE45827, GSE65194) to identify differentially expressed genes (DEGs) in TNBC.
- In vitro studies using TNBC cell lines (MDA-MB-231, MDA-MB-468) to assess UA's effects on proliferation, migration, invasion, cell cycle, and apoptosis.
- Molecular docking and pathway analysis (p53 signaling pathway) to identify key molecular targets (PLK1, CCNB1).
- Quantitative real-time PCR and Western blot to validate key gene and protein expression.
- In vivo studies to confirm UA's anti-tumor effects.
Main Results:
- Ursolic acid (UA) significantly reduced proliferation, migration, and invasion of TNBC cells in a dose-dependent manner.
- UA induced cell cycle arrest and apoptosis in TNBC cell lines.
- Bioinformatics analysis identified 724 DEGs, with PLK1 and CCNB1 highlighted as key targets involved in the p53 signaling pathway.
- UA treatment effectively inhibited TNBC tumor growth in vivo and downregulated PLK1 and CCNB1 protein expression by mediating the p53 signaling pathway.
Conclusions:
- Ursolic acid (UA) demonstrates significant anti-cancer activity against triple-negative breast cancer (TNBC).
- UA exerts its effects by targeting PLK1 and CCNB1 through the p53 signaling pathway, leading to inhibited cell growth and induced apoptosis.
- UA represents a promising therapeutic agent for TNBC, potentially through a multi-target therapeutic strategy.
