Abstract
<title>Abstract</title> <p>Tamoxifen resistance remains a significant therapeutic challenge in estrogen receptor-positive (ERα+) breast cancer. Although arginine metabolic reprogramming has been recognized as a driver of tumor progression, its role in tamoxifen resistance is not well understood. In this study, we demonstrate that the arginine-metabolizing enzyme ARG2 and its metabolite spermine are significantly elevated in tamoxifen-resistant cells. High ARG2 expression correlates with poor prognosis in ERα + patients. Silencing ARG2 genetically or inhibiting spermine synthesis pharmacologically using difluoromethylornithine (DFMO) effectively re-sensitizes resistant tumors to tamoxifen in vitro and in vivo. Mechanistically, we demonstrated that spermine inhibits apoptosis by suppressing the cleavage of Caspase2, revealing a previously unrecognized anti-apoptotic mechanism in resistant cells. Additionally, we revealed that POLR3A, a RNA polymerase III subunit, transcriptionally activates ARG2 expression, representing a non-canonical transcriptional function of POLR3A in cancer. In conclusion, this study establishes the POLR3A/ARG2/spermine axis as a critical driver of tamoxifen resistance and reveals a non-canonical transcriptional function of POLR3A. Importantly, our findings suggest DFMO, an existing anti-parasitic agent, as a promising combination therapeutic option for tamoxifen-resistant breast cancer.</p>