The Role of Metadherin in Inflammatory Breast Cancer Progression

Abstract

Inflammatory breast cancer (IBC) is the most lethal and aggressive form of breast cancer where patients have a 43% increased risk of death compared to women with non‐IBC. The lethality of IBC originates from its nature of invading the vascular and lymphatic systems, absence of a typical tumor mass, and the generation of tumor emboli. The arising challenges in IBC include the accurate and early diagnosis and the development of effective targeted therapies. A previous study investigated potential biomarkers involved in tumor spheroid integrity by characterizing IBC’s cell surface proteome. Plasma membrane proteins were identified via “stable isotope labeling with amino acids in cell culture” (SILAC) with subsequent mass spectrometry (MS)‐based quantitative proteomics analysis using the IBC cell line SUM‐149 vs. non‐ cancerous mammary epithelial cells, MCF10A. SILAC results showed overexpression of Metadherin (MTDH) in SUM‐149 cells (>2.0 fold change). Subsequently, we validated the overexpression of MTDH in SUM‐149 IBC cells, IBC tissues and in the emboli. MTDH is a cell adhesion molecule overexpressed in many cancer types, including breast cancer. MTDH promotes cancer progression by modulating various signaling pathways including NF‐kB, which is related to cell survival, proliferation, invasion and metastasis. Therefore, the aim of this study is to assess the functional role of MTDH in IBC progression. To elucidate the mechanism of action of MTDH in colony formation and tumor spheroid we silenced MTDH (CRISPR or shRNA) SUM‐149 and SUM‐190 IBC cells. We assessed the expression of MTDH by immunoblotting and immunofluorescence where we observed reduced MDTH levels. The number of colonies formed in SUM‐149 MTDH silenced cells was ~40% lower when compared to non‐silenced cells. Tumor spheroids of SUM‐149 and SUM‐190 MTDH silenced cells were smaller than non‐silenced cells. Aditionally, MTDH silencing results in a decrease in the phosphorylation of the p65 subunit of NF‐kB while no changes are observed in total protein abundance in SUM‐149 cells. We can conclude from our preliminary results that MTDH serves as a potential IBC target for IBC progression.Support or Funding InformationThis work was supported by NIH NIGMS #GM111171 (MMM), SGRP 2017‐00143 (MMM and GOS), NIMHD #MD007583 (MMM), GM103475 (UPR MMM), Title‐V‐PPOHA #P031M105050, Title‐V‐Cooperative #P031S130068 from the U.S. Dept. of Education and Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health #P20GM103475 (GOS).