Luteolin suppresses androgen receptor-positive triple-negative breast cancer cell proliferation and metastasis by epigenetic regulation of MMP9 expression via the AKT/mTOR signaling pathway.
Wu Han-Tsang,Lin Joseph,Liu Yi-En,Chen Hsiao-Fan,Hsu Kai-Wen,Lin Shu-Hsuan,Peng Kai-Yen,Lin Kuo-Juei,Hsieh Chang-Chi,Chen Dar-Ren
Phytomedicine : international journal of phytotherapy and phytopharmacology
BACKGROUND:Triple-negative breast cancer (TNBC) represents up to 20% of all breast cancers. This cancer lacks the expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. The current therapeutic strategy for patients with this subtype is the use of cytotoxic chemotherapy and surgery. Luteolin is a natural herbal flavonoid and a potential therapeutic candidate for multiple diseases. The use of a treatment that combines Chinese herbal medicine and western medicine is rising in Asia. PURPOSE:The present study evaluates the effects and molecular mechanisms involved with luteolin treatment and evaluates whether this herb affects androgen receptor-positive breast cancer cell proliferation or metastasis. STUDY DESIGN:In vitro evaluation of the effect of luteolin on androgen receptor-positive TNBC cell proliferation and metastasis METHODS: Cell viability analysis was used for the cytotoxicity test. Colony formation and Bromodeoxyuridine (BrdU) staining-based proliferation experiments were used for cell proliferation. Wound healing and transwell assays were used for in vitro migration/invasion. The RT-qPCR analysis was used for gene expression. Furthermore, ChIP-qPCR analysis was used for epigenetic modification of gene promoters. RESULTS:Luteolin significantly inhibited the proliferation and metastasis of androgen receptor-positive TNBC. Furthermore, luteolin inactivated the AKT/mTOR signaling pathway and reversed the epithelial-mesenchymal transition (EMT). The combination of luteolin and inhibitors of AKT/mTOR synergistically repressed an androgen receptor-positive TNBC cell proliferation and metastasis. Luteolin also downregulated MMP9 expression by decreasing the levels of the AKT/mTOR promoting H3K27Ac and H3K56A on the MMP9 promoter region. CONCLUSION:Our findings indicate that luteolin inhibited the proliferation and metastasis of androgen receptor-positive TNBC by regulating MMP9 expression through a reduction in the levels of AKT/mTOR-inducing H3K27Ac and H3K56Ac.
Luteolin suppresses epithelial-mesenchymal transition and migration of triple-negative breast cancer cells by inhibiting YAP/TAZ activity.
Cao Dai,Zhu Guo-Yuan,Lu Yan,Yang Aiping,Chen Die,Huang Hui-Jie,Peng Shu-Xian,Chen Li-Wen,Li Ying-Wei
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Triple-negative breast cancer (TNBC) is a highly lethal subtype of breast cancer associated with early relapse and metastasis. Epithelial to mesenchymal transition (EMT) plays pivotal roles in the progression of TNBC, including inducing cancer stem cell (CSC) properties, chemoresistance, tumor metastasis, and recurrence. Abnormally activated YAP/TAZ induces EMT in TNBC, making it a promising target for drug development. Our goal is to identify potential YAP/TAZ inhibitors from naturally derivative molecules and further study its effects on inhibiting EMT and metastasis of TNBC. In the current study, we demonstrate that luteolin significantly inhibits YAP/TAZ activity by promoting YAP/TAZ degradation in TNBC cells. Luteolin treatment leads to a decrease of mesenchymal markers and an increase of epithelial markers in both TNBC cells and TAZ-induced mesenchymal cells. Consistently, luteolin treatment inhibits cell migration in TNBC cells. Additionally, luteolin inhibits tumor growth in mice xenografted with TNBC cells. Collectively, our results support luteolin as a novel YAP/TAZ inhibitor for development as a new agent for the treatment of TNBC.