Lentinan inhibits breast cancer cell growth through the dual downregulation of tumor-promoting effectors CD133 and SCGB2A2.

Lentinan, a β-glucan extracted from Lentinus edodes, has been reported to exert potent antitumor activity. However, its underlying mechanism in breast cancer (BRCA) remains insufficiently elucidated. In this study, we investigated the direct antitumor effects of the water-extracted Lentinus edodes polysaccharide (WLNT) on human BRCA both in vitro and in vivo. Upon intravenous administration, WLNT reached the tumor site, peaked at 30 min and remained detectable for up to 2 h. Treatment with 1 mg/mL WLNT markedly suppressed tumor growth. Specifically, WLNT inhibits BRCA growth by downregulating the expression of CD133, a key marker of breast cancer stem cells. In addition, proteomic screening revealed that WLNT significantly downregulated the expression of SCGB2A2 (mammaglobin-A), whose levels are associated with the CD133 concentration in cells. Notably, SCGB2A2 was identified to promote BRCA cell proliferation, migration and xenograft tumor growth. We identified a novel anti-BRCA mechanism of WLNT in downregulating SCGB2A2 expression. Further investigation revealed that CD133 directly interacted with SCGB2A2 and accelerated its lysosomal degradation in cells under physiological conditions. WLNT competitively binds to CD133, inhibiting its interaction with SCGB2A2. In summary, our study demonstrates the critical role of the tumor-promoting effectors CD133 and SCGB2A2 in the anti-BRCA activity of WLNT, providing a new perspective for the study of the antitumor mechanism of lentinan.