No abstract

SELENOF, previously known as SEP15, is a selenoprotein that contains selenium in the form of the amino acid selenocysteine. Like other selenoproteins, the role for SELENOF in carcinogenesis has been investigated due to its altered expression compared to the corresponding normal tissue, its molecular function, and the association of genetic variations in the SELENOF gene to cancer risk or outcome. This review summarizes SELENOF’s discovery, structure, cellular localization, and expression. SELENOF belongs to a new family of thioredoxin-like proteins. Published data summarized here indicate a likely role for SELENOF in redox protein quality control, and in the regulation of lipids, glucose, and energy metabolism. Current evidence indicates that loss of SELENOF contributes to the development of prostate and breast cancer, while its loss may be protective against colon cancer. Additional investigation into SELENOF’s molecular mechanisms and its impact on cancer is warranted.

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.

African American women die of breast cancer at a much higher rate than Caucasian women. While the reasons behind this racial disparity are multifactorial, recent findings point to biological components that remain to be fully elucidated. We have recently identified SELENOF as a new tumor suppressor in breast cancer. Consequently, its reduction or loss may drive disease progression and poor outcome. Conversely, we have shown that restoring SELENOF expression elicited anti-tumor activity. Therefore, therapeutic strategies to mitigate the loss of SELENOF may be exploited to improve outcome for patients affected by the loss of SELENOF. Based on two different Chicago-based cohorts, we reported that the breast tumors from African Americans exhibited a 5-10-fold higher frequency of SELENOF single nucleotide polymorphisms (SNPs) compared to Caucasians; these genetic variations result in attenuated translation of SELENOF and thus reduced SELENOF levels. This is supported by preliminary data showing that SELENOF expression is significantly lower in breast tumors from African American patients compared to Caucasians, and lower SELENOF expression predicts shorter survival in these patients. Our goal is to elucidate the role of SELENOF in breast cancer and determine its impact on breast tumorigenesis. We hypothesize that either enhancing SELENOF levels or mimicking its downstream signaling can be exploited to mitigate the loss of SELENOF and elicit anti-tumor activity. Targeting tumor suppressors remains challenging. We identified the eukaryotic initiation factor 4a3 (eIF4a3) as a putative translational repressor of SELENOF, and our preliminary data shows that pharmacologic inhibition of eIF4a3 results in increased SELENOF protein levels. We also found that SELENOF overexpression induces cell death by engaging the inositol-requiring enzyme 1 (IRE1) to determine cell fate. The therapeutic strategies under investigation are likely to result in novel and more effective personalized medicine, and may help close the breast cancer racial disparity gap. Citation Format: Roudy C. Ekyalongo, Alexandra Zigrossi, Brenna Flowers, Alan M. Diamond, Irida Kastrati. SELENOF is a novel tumor suppressor and a new target to overcome breast cancer racial disparity [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C059.