Effects of Ganoderma lucidum (Reishi) on inflammatory breast cancer progression

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The anti-cancer effects of the individual components (immunomodulatory polysaccharides and cytotoxic triterpenes) of the medicinal mushroom Ganoderma lucidum (Reishi)have been shown to be effective in the treatment of inflammatory diseases and cancer. However, little is known about the effects of the whole mushroom in cancer (Reishi extract) as well as the role of Reishi in Inflammatory Breast Cancer (IBC). IBC is the most lethal and least understood form of locally advanced breast cancer that manifests itself with inflammatory-like symptoms and is associated with increased vasculogenesis and local invasion of the lymphatics. Genes involved in cell-cell adhesion (CHD1), angiogenesis and cell proliferation (VEGF, bFGF), cytokines (IL-6, IL-8), actin cytoskeletal rearrangement (RhoC), and the nuclear factor (NF)-kB and its targets are overexpressed in IBC. Reishi has been shown to inhibit proliferation, adhesion, migration, and invasion of cancer cells and downregulate farnesyl transferase and NF-kB activity. To test the hypothesis that Reishi may be effective against IBC progression and invasion, we tested the effect of whole Reishi extract on normal mammary epithelial (MCF-10A) and IBC (SUM-149) cell lines. Treatment with 0.25 mg/ml or 0.50 mg/ml of Reishi extract for 48 hr effectively inhibited proliferation of the IBC cell line SUM-149 but not the normal mammary epithelial cell line MCF10A. We tested the effect of Reishi on SUM-149 cell invasion in a 3-D Matrigel culture. Vehicle-treated SUM-149 cells invaded the Matrigel in spheroids that are reminiscent of the tumor cell emboli seen in IBC pathology. Reishi treatment reduced cell-cell attachments and decreased invasion of the Matrigel matrix. Investigation of gene expression in response to Reishi using RT² profiler cancer pathway finder PCR arrays, indicate that treatment with 0.50 mg/ml of Reishi extract for 8 hr significantly inhibits the expression of BCL-2, CDKN2A, TERT, PDGFB, and matrix metalloproteinase 9 (MMP-9) and induces IL-8 expression. A total of 52% of tumorigenesis genes were down-regulated in IBC cells treated with the Reishi extractcompared to those exposed to vehicle alone. Since MMPs are important for degradation of the extracellular matrix, we further investigated the effect of Reishi on MMP levels by gel zymography. Reishi at 0.5 mg/ml inhibited MMP-2 and MMP-9 levels compared to vehicle control. We conclude that Reishi inhibits IBC progression by reducing cell proliferation, preventing the formation of tumor emboli, and inhibiting invasion by reduced matrix MMP levels. Overall, these results demonstrate that Reishi extract is effective in inhibiting IBC progression, and is a potential natural therapeutic for women suffering with this deadly disease. This study was funded by S06 GM050695 and NIH/RCMI 2G12RR003035 to UCC.