Han-Tsang Wu1, Joseph Lin2, Yi-En Liu3, Hsiao-Fan Chen4, Kai-Wen Hsu5, Shu-Hsuan Lin6, Kai-Yen Peng6, Kuo-Juei Lin7, Chang-Chi Hsieh8, Dar-Ren Chen9. 1. Department of Cell and Tissue Engineering, Changhua Christian Hospital, Changhua 500, Taiwan. 2. Comprehensive Breast Cancer Center, Changhua Christian Hospital, Changhua 500, Taiwan; Department of Animal Science and Biotechnology, Tunghai University, Taichung 40704, Taiwan. 3. Cancer Research Center, Changhua Christian Hospital, Changhua 500, Taiwan. 4. Research Center for Cancer Biology, China Medical University, Taichung 404, Taiwan. 5. Research Center for Tumor Medical Science, China Medical University, Taichung 404, Taiwan. 6. Source Biotech Co., Ltd., Pingtung 905, Taiwan. 7. Department of Surgery, E-Da Hospital, I-Shou University, Kaohsiung, 824, Taiwan. 8. Department of Animal Science and Biotechnology, Tunghai University, Taichung 40704, Taiwan. Electronic address: cchsieh@thu.edu.tw. 9. Department of Cell and Tissue Engineering, Changhua Christian Hospital, Changhua 500, Taiwan; Comprehensive Breast Cancer Center, Changhua Christian Hospital, Changhua 500, Taiwan; Cancer Research Center, Changhua Christian Hospital, Changhua 500, Taiwan; School of Medicine, Chung Shan Medical University, Taichung, 40201, Taiwan. Electronic address: darren_chen@cch.org.tw.
Abstract
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.
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 humanepidermal 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.