Crosstalk between SELENOF and the unfolded protein response in breast epithelium dictates cell fate

SELENOF is an understudied selenoprotein that contains selenium in the form of selenocysteine. Our previous findings indicate that SELENOF likely functions as a tumor suppressor in breast cancer; however, its precise molecular role and regulatory mechanisms remain poorly understood. SELENOF localizes to the endoplasmic reticulum (ER) through a strong association with UDP-glucose glycoprotein glucosyltransferase 1 (UGGT1) and is thought to participate in protein folding quality control. Impaired protein folding efficiency leads to the accumulation of unfolded or misfolded proteins, thereby inducing ER stress and activating the unfolded protein response (UPR), an adaptive signaling network that restores ER homeostasis. Whether SELENOF modulates the UPR specifically in mammary epithelial cells and how this impacts cellular outcomes remain unknown. Here, we demonstrate that SELENOF establishes a feedforward regulatory loop with the inositol-requiring enzyme 1α (IRE1α) and X-box binding protein 1 (XBP1) arm of the UPR. SELENOF expression is upregulated by ER stress through the IRE1α-XBP1 pathway in normal immortalized human epithelial cells, murine mammary glands, and human breast cancer cells, thereby amplifying UPR signaling. In cancer cells, SELENOF overexpression exacerbates UPR activation, leading to IRE1α-dependent cell death. Conversely, SELENOF loss in normal breast epithelial cells limits the UPR to adaptive levels, allowing cells to evade senescence. Moreover, silencing UGGT1, a key enzyme in the glycan quality control pathway and interacting partner of SELENOF, reduced SELENOF protein levels and phenocopied its effects in limiting stress-induced activation of the IRE1-XBP1s axis of the UPR. Collectively, these findings identify SELENOF as a critical modulator of the UPR and highlight a complex and context-dependent role for SELENOF and IRE1α-UPR in breast tumorigenesis.