β‐Elemene Suppresses Proliferation, Migration, and Stemness in Triple‐Negative Breast Cancer by Inhibiting SIX‐1

Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited treatment options and poor prognosis. This study investigated the therapeutic potential of β-Elemene, a sesquiterpene from traditional Chinese medicine, against TNBC. We first confirmed that SIX-1 was significantly upregulated in TNBC tissues and cell lines. Our findings demonstrated that β-Elemene inhibited TNBC cell proliferation in a dose- and time-dependent manner. It also attenuated cell migration and invasion by reducing the expression and activity of MMP-2 and MMP-9. Furthermore, β-Elemene reversed epithelial-to-mesenchymal transition (EMT), as shown by the downregulation of N-cadherin, Snail, and TGF-β1, upregulation of E-cadherin, and a morphological shift towards an epithelial phenotype. The compound also diminished cancer stemness, evidenced by reduced spheroid formation and decreased expression of OCT4 and SOX2. Mechanistically, β-Elemene suppressed the β-Catenin/ID2 signaling pathway, an effect that was reversed by SIX-1 overexpression. In conclusion, β-Elemene suppresses TNBC proliferation, migration, invasion, and stemness in vitro by modulating the SIX-1/β-Catenin/ID2 axis, suggesting its promise as a candidate for further therapeutic development.