Abstract
Purpose: Due to a lack of recognized molecular targets for therapy, patients with triple-negative breast cancer (TNBC), unlike other subtypes of breast cancers, generally have not benefited from the advances made with targeted agents. The CXCR4/SDF-1 axis is involved in tumor growth and metastasis of TNBC. Therefore, down-regulation of the expression of CXCR4 in cancer cells is a potential therapeutic strategy for inhibiting primary tumor growth and metastasis of TNBC. In order to identify bioactive compounds that inhibit the expression of CXCR4 in traditional Chinese medicines, we investigated the capacity of saikosaponin A (SSA), one of the active ingredients isolated from Radix bupleuri, to affect CXCR4 expression and function in TNBC cells.Methods: Analyses of cell growth, migration, invasion, and protein expression were performed. Knockdowns by small interfering RNA (siRNA) and non-invasive bioluminescence were also used.Results: SSA reduced proliferation and colony formation of SUM149 and MDA-MB-231 cells. SSA inhibited migration and invasion of TNBC cells. For mice, SSA inhibited primary tumor growth and reduced lung metastasis of highly metastatic, triple-negative 4T1-luc cells. SSA inhibited CXCR4 expression but did not regulate CXCR7 expression in vitro and in vivo. The inhibitory effects on the migration and invasion of TNBC cells were reversed by down-regulation of CXCR4 expression. In addition, SSA inactivated the Akt/mTOR signaling pathway and inhibited MMP-9 and MMP-2 expression.Conclusions: The results show that SSA exerts an anti-TNBC effect through the inhibition of CXCR4 expression and thus has the potential to be a candidate therapeutic agent for TNBC patients.
Highlights
Breast cancer is a major risk factor for women’s health
The effects of saikosaponin A (SSA) on the proliferation of triple-negative breast cancer (TNBC) cells were evaluated with Cell Counting Kit-8 (CCK-8) kits
To exclude deviations in the results of the subsequent experiments that might be caused by the cytotoxicity of lowdose SSA, flow cytometry (Data Sheet 1) was performed after staining the cells with Annexin V-FITC/propidium iodide (PI) (BD, USA)
Summary
Breast cancer is a major risk factor for women’s health. In the United States in 2019, it was estimated that 268,600 women would be diagnosed with breast cancer, accounting for 30% of all new cancer diagnoses in women [1]. Compared with Western countries, the incidence of breast cancer in China is relatively low. With the acceleration of urbanization in China, the incidence of breast cancer has increased rapidly since the 1990s, and the number of cases will reach 2.5 million by 2021 [2]. Of all of the subtypes of breast cancer, triple-negative breast cancer (TNBC) has the most lethal characteristics and is associated with a poor prognosis, lacking expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 (HER-2/neu) [3]. There is a relatively high response to cytotoxic chemotherapy, local recurrence in TNBC patients is more likely to cause lung and brain metastases, leading to death [5]
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