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.