SLC30A1, SLC30A5, and SLC30A9 transporters play crucial role in ligand-independent activation of ESR1 signalling in breast cancer cells via modulation of AKT activity by zinc.

Zinc is essential for cellular homeostasis and acts both as a structural element and a secondary messenger in intracellular signalling. While the role of SLC39 (former ZIP) family transporters in breast cancer biology is intensively studied, the signalling function of SLC30 family transporters (former ZnT) remains insufficiently explored. This study investigates the involvement of SLC30 transporters in oestrogen receptor-positive (ER+) breast cancer. Bioinformatic and experimental analyses revealed that SLC30 transporters, particularly SLC30A1, SLC30A5, and SLC30A9, regulate the PTP/AKT/ESR1 pathway, contributing to hormone-independent ESR1 activation. Zn-dependent inhibition of PTP phosphatases modulates kinase signalling, promoting proliferation. Notably, high SLC30 expression correlates with improved survival, but serves as a negative prognostic marker under tamoxifen treatment. Here, we evidence that ESR1 directly represses SLC30 transcription and that zinc transporters form a regulatory feedback loop sustaining ER+ breast tumour progression. These findings position SLC30 transporters as active participants in signalling cascades, offering novel targets for therapeutic intervention in ER+ breast cancer.