Zip3 plays a major role in zinc uptake into mammary epithelial cells and is regulated by prolactin.

During lactation, a substantial amount of Zn(2+) is transferred by the mammary gland from the maternal circulation into milk; thus secretory mammary epithelial cells must tightly regulate Zn(2+) transport to ensure optimal Zn(2+) transfer to the suckling neonate. To date, six Zn(2+) import proteins (Zip1-6) have been identified; however, Zip3 expression is restricted to tissues with unique requirements for Zn(2+), such as the mammary gland, which suggests that it may play a specialized role in this tissue. In the present study, we have used a unique mammary epithelial cell model (HC11) to characterize the role of Zip3 in mammary epithelial cell Zn(2+) transport. Confocal microscopy demonstrated that Zip3 is localized to the cell surface in mammary epithelial cells and transiently relocalized to an intracellular compartment in cells with a secretory phenotype. Total (65)Zn transport was higher in secreting cells, while gene silencing of Zip3 decreased (65)Zn uptake into mammary epithelial cells, particularly in those with a secretory phenotype. Finally, reduced expression of Zip3 ultimately resulted in cell death, indicating that mammary epithelial cells have a unique requirement for Zip3-mediated Zn(2+) import, which may reflect the unique requirement for Zn(2+) of this highly specialized cell type and thus provides a physiological explanation for the restricted tissue distribution of this Zn(2+) importer.