Mechanisms of Antibreast Cancer Activity of Terpenoids from the Fruiting Body of Antrodia cinnamomea in Cellular and Mice Models

Antrodia cinnamomea (A. cinnamomea), an edible medicinal fungus, contains a unique class of terpenoids. In this work, we studied the activity of terpenoid-rich diethyl ether extract (termed AC-DE) for the treatment of drug-resistant triple-negative breast cancer (TNBC). In vitro assays using both 2D and 3D models demonstrated that AC-DE exhibited potent, dose-dependent cytotoxicity across multiple cancer cell lines, significantly inducing apoptosis and inhibiting the proliferation, migration, and invasion of MDA-MB-231 breast cancer cells. Mechanistic studies demonstrated that AC-DE induced mitochondrial dysfunction by upregulating pro-apoptotic proteins, including Bax, caspase-9, caspase-3, and cytochrome c, while downregulating the antiapoptotic protein Bcl-2. In addition, AC-DE suppressed the PI3K/AKT/mTOR signaling pathway, suggesting a dual mechanism involving both mitochondrial and signaling pathway regulation. In vivo, AC-DE (25, 50, and 100 mg/kg every other day) significantly suppressed tumor growth in MDA-MB-231 xenograft-bearing nude mice. Collectively, these findings highlight that AC-DE extract is promising as a functional food or therapeutic ingredient for managing drug-resistant TNBC.