# Opposing Roles for ATP13A2 and ATP13A3 in Breast Cancer Subtype-Specific Polyamine Homeostasis

## TL;DR

This study explores how polyamine regulation differs across breast cancer subtypes and identifies ATP13A2 and ATP13A3 as key players with opposing roles in patient outcomes.

## Contribution

The study reveals subtype-specific roles of ATP13A2 and ATP13A3 in polyamine transport and prognosis in breast cancer.

## Key findings

- Polyamine transport contributes to heterogeneity across and within breast cancer subtypes.
- ATP13A3 is an adverse prognostic marker in basal-like breast cancer.
- ATP13A2 is associated with better patient survival, showing opposing roles to ATP13A3.

## Abstract

Polyamine homeostasis is essential for normal cellular function and is maintained through coordinated regulation of polyamine biosynthesis, catabolism, and transport. This balance is frequently disrupted in breast cancer, a biologically heterogeneous disease comprising distinct molecular subtypes. However, whether polyamine metabolism and transport are differentially regulated across breast cancer subtypes remains poorly defined. Here, we systematically interrogate polyamine homeostasis across representative breast cancer subtypes by integrating cell line profiling combined with analysis of publicly available patient datasets. We found subtype-associated differences across the polyamine pathway and identify polyamine transport as a key contributor to inter- and intra-subtype heterogeneity. Notably, ATP13A3 emerges as a previously unrecognized adverse prognostic marker, particularly in basal-like breast cancer, where its expression associates with proliferative and oncogenic signaling programs. In contrast, ATP13A2 shows an opposing association with patient survival, suggesting divergent functional roles for these closely related transporters. Together, our findings demonstrate that polyamine regulation in breast cancer is highly subtype dependent and highlight the importance of molecular stratification when considering polyamine-directed therapeutic strategies in breast cancer.