Abstract 1498: SELENOF maintains proteostasis through UPR-IRE1α axis in breast cancer

Abstract Background: SELENOF is an understudied selenoprotein that incorporates selenium in the form of selenocysteine. Our lab’s investigation into SELENOF’s function in breast cancer indicates that it is likely a tumor suppressor. SELENOF resides in the endoplasmic reticulum (ER) and has been hypothesized to assist in protein folding, specifically disulfide-bond formation. Disruption of protein folding efficiency leads to the accumulation of misfolded proteins, a process referred as EnR stress. In turn, the unfolded protein response (UPR) is triggered to relieve EnR stress and to restore protein processing functions. In cancer, UPR is a double edge sword. To meet the challenges of rapid proliferation, cancer cells exploit this intrinsic adaptive mechanism of UPR. However, with prolonged and unresolved EnR stress, the cell switches UPR from an adaptive response to a terminal death-inducing response. We hypothesize that SELENOF may play a role in UPR stress resolution, and how this affects breast cancer initiation of progression remains to be determined. Objective: Our study aims to determine the crosstalk between SELENOF and EnR using normal mammary gland tissue and breast cancer models. Results: SELENOF levels were manipulated by overexpression or knockout in normal breast epithelial cells and in breast cancer cell lines. Loss of SELENOF does not change baseline UPR measured by Thioflavin T staining and EnR stress markers include IRE1a phosphorylation and XBP1 mRNA splicing. Instead, overexpression of SELENOF increased UPR. We also determined that the IRE1-XPB1 axis required, but not the other two, Upon induction of EnR stress using Tunicamycin, Thapsigargin, we find that SELENOF levels is increased via IRE1-XBP1, thus uncovering a crosstalk between UPR and SELENOF. Furthermore, loss of SELENOF reduces the overall UPR. These findings were validated in vivo using wild type and SELENOF knockout mice. Conclusion: Our findings establish a feed-forward model between UPR and SELENOF; SELENOF level increase upon UPR induction to amplify the UPR response towards terminal UPR. Loss of SELENOF restricts UPR response within adaptive levels to bypass cell death. This may provide a mechanism for cancer cells to survive while coping with higher proteotoxic stress. Citation Format: An Zhang, Irida Kastrati. SELENOF maintains proteostasis through UPR-IRE1α axis in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1498.