Abstract C059: SELENOF is a novel tumor suppressor and a new target to overcome breast cancer racial disparity

Abstract

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.