Abstract 1987: Ganoderma lucidum (Reishi) suppresses key protein synthesis initiation molecules in inflammatory breast cancer

Abstract

Abstract Inflammatory breast cancer (IBC) is an aggressive and lethal type of breast cancer. IBC's lethality originates from its nature of invading the lymphatic system and to the absence of a palpable tumor mass. Pathogenic properties of IBC result in part from deregulation of the eukaryotic translation initiation factor (eIF4G), which is activated via the mammalian target of rapamycin (mTOR) pathway. Active mTOR signaling liberates eukaryotic translation initiation factor 4E (eIF4E) through the hierarchical phosphorylation of eIF4E binding protein (4E-BP). When hypophosphorylated, 4E-BP associates with eIF4E, preventing eIF4E from binding eIF4G, blocking the formation of the eIF4F translation initiation complex; thus, impeding protein translation. Therefore therapeutics that target eIF4G in IBC are of great interest. Ganoderma lucidum (Reishi) is a medicinal mushroom used to prevent and treat many diseases including cancer. We recently reported that Reishi inhibits eIF4G expression after 24h of treatment in the SUM-149 IBC patient derived cell line. Therefore, we investigated the therapeutic potential of Reishi mushroom in IBC cells in vitro and in vivo, focusing on the regulation of mTOR and direct downstream effectors: 4E-BP1 and the ribosomal protein p70S6K. Herein, we show that Reishi treatment of SUM-149 cells impacts protein synthesis initiation via inhibition of the mTOR pathway leading to hypophosphorylation of 4E-BP1. Accordingly, Reishi downregulates mTOR protein levels, 4E-BP1 phosphorylation, maintains eIF4E levels and decreases p70S6k and eIF4G expression, potentially leading to reduced eIF4F translation initiation complex levels after 6h of treatment. To further investigate Reishi's therapeutic effects in vivo, we studied IBC progression of SUM-149 subcutaneous tumors in severe combined immunocompromised (SCID) mice. Following tumor establishment, mice were gavaged every day with vehicle or Reishi at 28mg/kg BW for 13 weeks. Tumor progression was quantified by caliper measurements, followed by analysis of excised organs for protein expression. Results show that Reishi significantly reduced tumor growth by 58% compared to vehicle controls. Moreover, mTOR, eIF4E, eIF4G, E-cadherin, p4E-BP1 and p70S6k expression decreases in the SUM-149 tumors from mice treated with Reishi. Our results provide evidence that Reishi suppresses key molecules that are important for protein synthesis initiation in IBC, thus highlighting the potential of Reishi as a natural anti-IBC-therapeutic. This project was sponsored by Title V PPOHA grant number P031M105050 from the US Dept of Education to UCC, and NIH/RCMI 2G12RR003035 to UCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1987. doi:1538-7445.AM2012-1987