ZnT2‐mediated Zn Transport Modulates Prolactin Stability and Secretion to Maintain Lactation

Abstract

Prolactin (PRL), secreted from lactotrophs into circulation and from mammary epithelial cells (MECs) into milk, regulates mammary gland (MG) differentiation, milk production and secretion during lactation. Zinc (Zn) is implicated in PRL oligimerization (stability) and storage in secretory vesicles. We previously found that in MECs, the Zn transporter ZnT2 imports Zn into vesicles for secretion into milk and ZnT2 mutations in women result in substantial reduction in milk Zn levels. To test the hypothesis that ZnT2 provides Zn for PRL stability and thus modulates MG function during lactation, we used ZnT2‐null mice and studies of MECs in vitro. Lactating ZnT2‐null mice had substantial defects in MG architecture and MEC sub‐structure, reduced Stat5 activation, impaired milk secretion and 60% less milk PRL. MECs in vitro showed that ZnT2 and PRL were co‐localized in vesicles. ZnT2‐attenuated MECs had significantly greater intracellular PRL but reduced PRL oligimerization and secretion compared to ZnT2‐expressing cells, suggesting that ZnT2‐mediated Zn transport regulates PRL stability and secretion. Moreover, ZnT2‐attenuation eliminated the ability to activate Stat5 and increase expression and secretion of β‐casein. Finally, breastfeeding women with a common loss‐of‐function variant in ZnT2 (D103E) had significantly less milk PRL concurrent with significantly greater milk sodium, a hallmark of MG dysfunction. Taken together, these results establish that ZnT2 is critical for regulating PRL stability, storage and secretion in the MG to maintain the differentiated epithelium and milk secretion during lactation.