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Simple Summary: tRF-27 has been identified as upregulated in both naïve trastuzumab-resistant HER2-positive breast cancer cells and patient samples, positioning it as a potential biomarker. However, the underlying mechanisms of this upregulation remain unclear. This study proposes that the abnormal transcription of specific tRNA-Cys-GCA isodecoders in naïve trastuzumab-resistant cells might contribute to the accumulation of tRF-27. Additionally, the reduction in H3K27me3 modifications at these tRNA genes, attributed to imbalances in histone modification enzymes, appears to influence tRNA transcription alterations. Building upon these findings, our research demonstrates that the application of a demethylase inhibitor may offer a potential strategy to overcome trastuzumab resistance. tRNA-derived fragments (tRFs) play crucial roles in cancer progression. Among them, tRF-27 has been identified as a key factor in promoting naïve trastuzumab resistance in HER2-positive breast cancer. However, the origin of tRF-27 remains uncertain. In this study, we propose that the upregulated expression of specific cysteine tRNAs may lead to the increased accumulation of tRF-27 in trastuzumab-resistant JIMT1 cells. Mechanistically, the reduced inhibitory H3K27me3 modification at the promoter regions of tRF-27-related tRNA genes in JIMT1 cells, potentially resulting from decreased EZH2 and increased KDM6A activity, may be a critical factor stimulating the transcriptional activity of these tRNA genes. Our research offers fresh insights into the mechanisms underlying elevated tRF-27 levels in trastuzumab-resistant breast cancer cells and suggests potential strategies to mitigate trastuzumab resistance in clinical treatments. [ABSTRACT FROM AUTHOR]

Simple Summary: While the prognosis of hormone receptor-positive (HR+) breast cancer has been significantly improved, tamoxifen resistance remains a challenge in the treatment of HR+ breast cancer. This study identified that tRF-16-K8J7K1B, a novel small ncRNA derived from the 3′-end of tRNAAla-TGC, was highly expressed in tamoxifen-resistant cells compared to parental cells. Moreover, extracellular tRF-16-K8J7K1B confers tamoxifen resistance via incorporation into exosomes and then degrades the expression of apoptosis-related proteins, reducing the proportion of drug-induced cell apoptosis. Therefore, we propose that exosomal tRF-16-K8J7K1B could be a potential predictive biomarker and therapeutic target for overcoming tamoxifen resistance. Tamoxifen resistance remains a challenge in hormone receptor-positive (HR+) breast cancer. Recent evidence suggests that transfer ribonucleic acid (tRNA)-derived fragments play pivotal roles in the occurrence and development of various tumors. However, the relationship between tRNA-derived fragments and tamoxifen resistance remains unclear. In this study, we found that the expression of tRF-16-K8J7K1B was upregulated in tamoxifen-resistant cells in comparison with tamoxifen-sensitive cells. Higher levels of tRF-16-K8J7K1B were associated with shorter disease-free survival in HR+ breast cancer. Overexpression of tRF-16-K8J7K1B promotes tamoxifen resistance. Moreover, extracellular tRF-16-K8J7K1B could be packaged into exosomes and could disseminate tamoxifen resistance to recipient cells. Mechanistically, exosomal tRF-16-K8J7K1B downregulates the expression of apoptosis-related proteins, such as caspase 3 and poly (ADP-ribose) polymerase, by targeting tumor necrosis factor-related apoptosis-inducing ligand in receptor cells, thereby reducing drug-induced cell apoptosis. Therapeutically, the inhibition of exosomal tRF-16-K8J7K1B increases the sensitivity of breast cancer cells to tamoxifen in vivo. These data demonstrate that exosomal tRF-16-K8J7K1B may be a novel therapeutic target to overcome tamoxifen resistance in HR+ breast cancer. [ABSTRACT FROM AUTHOR]