Molecular Characterization of the Role of Metadherin in Promoting Breast Cancer Metastasis

Abstract

The Metadherin gene (MTDH) is amplified in breast cancer and associated with increased lung metastasis. Previous studies have identified MTDH’s binding partner, SND1, and the functional role of their interaction during tumor initiation. However, MTDH’s role in metastasis was largely uncharacterized. In the current study, we demonstrate that MTDH expression enables tumor cells to evade immune recognition and destruction. Using mouse models, we show that the immune cells infiltrating MTDH+ primary tumors express CTLA-4 and PD-1 on their surface, which are characteristic of regulatory T-cells. Mechanistically, T-cells exposed to MTDH+ tumor cells show reduced expression of genes associated with T-cell activation, and increased expression of genes involved with T-cell suppression. In particular, the reduced expression of protein arginine methyltransferase 1 (PRMT-1) in T-cells co-cultured with MTDH+ tumor cells leads to decreased secretion of CXCL9 and IFN-γ—cytokines important for the anti-tumor immune response. Future experiments are needed to elucidate whether MTDH+ tumor cells exert their immunosuppressive effects through a T-cell receptor-dependent mechanism or through secreting soluble factors. The mechanistic understanding of how MTDH shapes the immune response will allow us to identify components of the pathway that can be clinically targeted, providing novel treatment options to breast cancer patients.