Introduction
Breast cancer is the most common type of diagnosed cancer among women worldwide. According to the statistics, approximately 2,088,849 new breast cancer cases were detected and about 626,679 patients died from breast cancer in 2018 worldwide.(Bray, Ferlay, Soerjomataram, Siegel, Torre & Jemal, 2018) Even though there have been significant developments in regard to the survival rates of patients with breast cancer, this disease remains a tremendous threat to women’s health. This is particularly true for patients with “triple-negative breast cancer” (TNBC), which is defined by the lack of expression of the estrogen receptor (ER), progesterone (PR), and human epidermal growth factor receptor 2 (HER2). TNBC accounts for 11.2-16.3% of all breast cancers and is insensitive to hormonal therapy or HER2-targeted drugs.(Sharpe et al., 2011; Siegel, Miller & Jemal, 2016; Zhao et al., 2014) Furthermore, breast cancer metastasis is a predominant cause of clinical mortality, occurring when the tumor cells migrate from the primary tumor foci to the distant sites.(Chen et al., 2013) Commonly, an eighth of all diagnosed breast cancers are invasive/metastatic.(Chambers, Groom & MacDonald, 2002) However, there are currently few effective drugs available to treat metastatic breast cancer and improve survival in these patients.(Steeg, 2016) Hence, novel strategies are urgently needed to improve the anti-tumor and anti-metastasis therapies targeting TNBC.
Nuclear factor-kappa B (NF-κB) was discovered in 1986 as a B-cell–specific transcription factor and is a key regulator that promotes cell proliferation, suppresses apoptosis, accelerates cell migration and invasion, and stimulates metastasis and angiogenesis.(Sen & Baltimore, 1986; Zhang, Lenardo & Baltimore, 2017) Activation of NF-κB is usually rapidly triggered by infections, DNA damage, or oxidative stress,(Karin & Greten, 2005) and it has been reported that NF-κB is constitutively active in both tumor cells and the tumor microenvironment, including in breast cancer, ovarian cancer, colorectal cancer, and others.(Staudt, 2010) Activated NF-κB plays a key role in cancer metastasis, as NF-κB can directly induce metastatic dissemination via the epithelial-mesenchymal transition (EMT) and promote tumor cell escape from the primary tumor, which leads to dissemination via the blood or lymphatic vessels and colonization of distant organs, including the lungs, bone, brain, and lymph nodes.(Fidler & Poste, 2008; Karagiannis et al., 2017) In addition, NF-κB activation can enhance cancer cell migration and invasion via induction of matrix-degrading enzymes, such as MMP2 and MMP9.(Huang, Pettaway, Uehara, Bucana & Fidler, 2001) What’s more, NF-κB is closely related to tumor immunosuppressive microenvironment. Existing evidences revealed that activation of NF-κB directly participates in proliferation of regulatory T cells (Treg) and transcription of PD-L1(Maeda et al., 2018; Vanamee & Faustman, 2017). Inhibition of NF-κB can relieve tumor immunosuppressive microenvironment and enhance tumor immune therapy. Therefore, targeting of NF-κB might be a promising therapeutic approach for the treatment of breast cancer. However, there are few oral small molecular drugs that can effectively inhibit the activation of NF-κB that have been approved for use in clinical application.
Plant-derived natural drugs play an important role in the development of cancer chemotherapies.(Amin, Kucuk, Khuri & Shin, 2009) It has been reported that over 60% of the presently used anti-cancer drugs are directly or indirectly derived from natural sources, including plants, marine organisms, and micro-organisms.(Shinde, Banerjee & Mandhare, 2019; Zhang, Chen, Ouyang, Cheng & Liu, 2012) Small molecules, such as paclitaxel, vincristine, and camptothecin, which are derived from natural plants, have been used successfully as anti-cancer drugs.(Chen et al., 2016) However, the demand for further discovery of novel therapeutic molecules derived from natural sources for cancer treatment is a never-ending venture.
Icariin, a prenylated flavonol glycoside, which is extracted from the medical plantHerba Epimedii (Fig. 1A), has demonstrated numerous pharmacological actions, including aphrodisiac, osteogenic, antidepressant, cardiovascular protective, and immunomodulatory activities.(He, Sun, Yang, Zhang & Kabelitz, 1995; Pan, Kong, Li, Xia, Kung & Jiang, 2007; Xu & Huang, 2007) It has been reported that icariin can serve as an effective NF-κB inhibitor to alleviated murine lupus nephritis and improves fanconi anemia hematopoietic stem cell function.(Li, Li, Cole, McLaughlin & Du, 2018; Su, Ye, You, Ni, Chen & Li, 2018) In recent years, studies have demonstrated the anti-cancer effect of icariin against osteosarcoma, prostate, lung, and gastric cancer cells.(Geng, Yang, Zhang & Kong, 2014; Lee et al., 2009; Wang et al., 2010) However, the function of icariin in regard to breast cancer and its related molecular mechanisms have not yet been investigated. Therefore, considering the role of NF-κB in breast cancer, we hypothesized that icariin might be a promising candidate for breast cancer treatment. In this study, we demonstrated that icariin acts as an effective agent against breast cancer cells bothin vitro and in vivo , and the reactive oxygen species (ROS)-dependent mitochondrial pathway and SIRT6/NF-κB/EMT pathway are likely involved in icariin-mediated apoptosis and migration. Our findings suggest that icariin could serve as a potential agent for the treatment of breast cancer.