Seesaw configuration of the ODC-OAZ1-AZIN1 axis governs sensitivity to polyamine-targeting inhibitors of breast cancer cells

Abstract

Polyamines are endogenous metabolites crucial for various cellular functions, and maintaining their cellular levels is critical for normal cell survival and fate. Polyamine homeostasis is managed by a complex metabolic network, wherein the ODC-OAZ1-AZIN1 protein-protein interaction axis plays a central role in regulating polyamine synthesis and membrane transport. While existing research has established that polyamine-targeted inhibitors (PTIs) significantly perturb this axis in various cancers, and that different breast cancer subtypes display distinct PTI sensitivities, the fundamental mechanism of drug sensitivity difference has remained poorly understood. Here, we combine large-scale bioinformatic analysis with comprehensive experimental verification to reveal a polarized seesaw configuration of the ODC-OAZ1-AZIN1 axis across diverse tumor types, including breast cancer. We show that this seesaw configuration is not only distinct across breast cancer subtypes but also associated with unique cellular states. Furthermore, we reveal that this configuration underpins the distinct sensitivity profiles of these subtypes to both single and combination treatments of PTIs. Crucially, we demonstrate that targeted re-configuration of this axis can shift the drug sensitivity of resistant cells. This study provides the first systematic mechanistic framework linking the configuration of the ODC-OAZ1-AZIN1 axis to PTI sensitivity, thereby providing a configuration-based framework for rational selection of PTI combination regimens and new personalized therapeutic strategies in breast cancer.