Ganoderma lucidum extract decreases inflammatory breast cancer progression via translational control

Abstract

Inflammatory Breast Cancer is a highly aggressive and chemo/radiation resistant cancer in which cells invade the vascular and lymphatic systems via generation of tumor emboli; a process regulated by selective mRNA translation. Accordingly, our objective is to characterize the role of Ganoderma lucidum extract (GLE) in translational regulation. In IBC, the mammalian target of rapamycin (mTOR) pathway is hyperactivated, while the eukaryotic initiation factor 4G (eIF4GI) is overexpressed. mTOR regulates translation initiation, and together with eIF4G, both regulate resistance to therapy of IBC cells, cancer cell survival and invasion. We previously showed that GLE reduces cap‐dependent mRNA translation in part through the inactivation (dephosphorylation) of mTOR, thereby activating eIF4E sequestration in IBC cells and tumors. GLE also induces cancer cell death, inhibits cancer cell invasion and synergizes with conventional chemotherapy to reduce IBC progression, while not affecting non‐cancerous cells. However the role of GLE on translational control in advanced BC has not been studied. We hypothesize that GLE regulates translation via translation initiation inhibition. Genome‐wide translation and transcription profiling was conducted in SUM‐149 IBC cells treated with vehicle or GLE for 24h. Analysis of actively translated mRNAs revealed that 689 genes showed differential expression by GLE treatment. Ingenuity pathway analysis revealed that the majority of these mRNAs are involved in the eIF2 and mTOR pathways, which control translation. Future directions include performing quantitative PCR arrays to validate the microarray results. This study is relevant to our long‐term goal of contributing to the discovery of therapeutics to reduce mortality of IBC.Support or Funding InformationThis project was sponsored by Title V PPOHA and Title‐V‐Cooperative #P031S130068 US Department of Education #P031M105050, NIH/RCMI #8G12MD007583, NIH/NIGMS #1SC3GM111171 to MMM, NCI #R01CA178509 to RJS, and the Breast Cancer Research Foundation (BCRF‐16–143) to RJS. The content is solely the responsibility of the authors and does not necessarily represent the official views of the supporting agencies.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.