Tanshinone IIA inhibits malignant progression in a spontaneous breast cancer mouse model by attenuating tissue factor-mediated angiogenesis.

Abstract

<p>INTRODUCTION: As a classic botanical drug, Salvia miltiorrhiza Bunge has long been used to promote blood circulation and remove blood stasis. Tanshinone IIA (Tan IIA), a major bioactive diterpenoid derived from its roots, shows promising therapeutic potential, but its chemopreventive actions against early tumor progression have not been fully clarified. This study aims to comprehensively examine the chemopreventive potential of Tan IIA, specifically focusing on the poorly studied adenoma-to-early-carcinoma transition in breast cancer, and elucidate its underlying anti-angiogenic mechanisms. METHODS: We adopted the mouse mammary tumor virus-polyoma virus middle T antigen (MMTV-PyMT) transgenic mouse model, which recapitulates the natural progression of spontaneous breast tumorigenesis. A combination of pharmacokinetic analysis, network pharmacology, in vivo histopathology, immunofluorescence (IF) staining, multiple angiogenesis assays, and molecular experiments, including qPCR, Western blot, and cellular thermal shift assay (CETSA), was applied for comprehensive evaluation. RESULTS: Our results demonstrated that Tan IIA markedly delayed the malignant transformation of benign mammary tumors. Pharmacokinetic characterization confirmed the favorable in vivo bioavailability of Tan IIA and its metabolites. Mechanistically, Tan IIA significantly downregulated tissue factor (TF), a critical driver of tumor angiogenesis. This reduction in TF expression was accompanied by decreased levels of vascular endothelial growth factor A (VEGFA) and other pro-angiogenic factors. DISCUSSION: Our work reveals that Tan IIA exerts prominent chemopreventive effects against breast precancerous lesions, mainly by suppressing TF-mediated angiogenesis, indicating its great promise as a candidate agent for early breast cancer intervention.</p>