The POLR3A/ARG2/Spermine axis drives malignant progression of tamoxifen-resistant breast cancer

Tamoxifen resistance was the principal cause for the failure of endocrine therapy in ERα-positive breast cancer. It has been reported that tamoxifen-resistant breast cancer cells exhibit various malignant phenotypes, including enhanced malignant proliferation capacity and anti-apoptotic ability. Meanwhile, arginine metabolic reprogramming has been reported to be associated with the malignant progression of various tumors. In this study, we found the correlation between arginine metabolic reprogramming and tamoxifen resistance in breast cancer by multi-omics analysis including transcriptome and metabolomics. Further studies showed that the key enzyme ARG2 in arginine metabolic pathway was significantly upregulated in tamoxifen-resistant breast cancer cells and was associated with poor prognosis of breast cancer. Functional studies demonstrated that inhibiting the expression or function of ARG2 could markedly suppress the malignant phenotype of tamoxifen-resistant breast cancer cells in both animal and cell models. Molecular mechanism studies further clarified that the transcription factor POLR3A was involved in the transcriptional regulation of ARG2. Overall, this research initially uncovered the role of the POLR3A/ARG2/spermine regulatory axis in tamoxifen resistance of breast cancer, offering novel therapeutic strategies and new drug targets for tamoxifen-resistant breast cancer.