SELENOF Controls Proliferation and Cell Death in Breast-Derived Immortalized and Cancer Cells

SIMPLE SUMMARY: Selenoproteins are an elite family of proteins containing selenium in the form of the rare amino acid selenocysteine. SELENOF, formerly known as SEP15, is one of the selenoproteins that is highly sensitive to bioavailable selenium, which itself correlates with survival of breast cancer patients. SELENOF was reported to be lower or lost in aggressive breast tumors. Based on this evidence, SELENOF-driven functions and phenotypes were examined in normal breast epithelial and breast cancer cells to better understand the role of SELENOF in breast cancer. We found that loss of SELENOF confers features of oncogenic transformation while the opposite features are observed with its overexpression. These findings indicate that loss of SELENOF observed in breast tumors contributes to breast tumorigenesis. ABSTRACT: SELENOF expression is significantly lower in aggressive breast tumors compared to normal tissue, indicating that its reduction or loss may drive breast tumorigenesis. Deletion of SELENOF in non-tumorigenic immortalized breast epithelial MCF-10A cells resulted in enhanced proliferation, both in adherent culture and matrix-assisted three-dimmensional (3D) growth. Modulation of SELENOF in vitro through deletion or overexpression corresponded to changes in the cell-cycle regulators p21 and p27, which is consistent with breast tumor expression data from the METABRIC patient database. Together, these findings indicate that SELENOF affects both proliferation and cell death in normal epithelial and breast cancer cells, largely through the regulation of p21 and p27. In glandular cancers like breast cancer, the filling of luminal space is one of the hallmarks of early tumorigenesis. Loss of SELENOF abrogated apoptosis and autophagy, which are required for the formation of hollow acini in MCF-10A cells in matrix-assisted 3D growth, resulting in luminal filling. Conversely, overexpression of SELENOF induced cell death via apoptosis and autophagy. In conclusion, these findings are consistent with the notion that SELENOF is a breast tumor suppressor, and its loss contributes to breast cancer etiology.