Essential role for ZnT2-mediated zinc transport in mammary gland development and function during lactation [Cell Biology]

April 7th, 2015 by Lee, S., Hennigar, S. R., Alam, S., Nishida, K., Kelleher, S. L.

The zinc (Zn) transporter ZnT2 (SLC30A2) imports Zn into vesicles in secreting mammary epithelial cells (MECs) and is critical for Zn efflux into milk during lactation. Recent studies show that ZnT2 also imports Zn into mitochondria and is expressed in the non-lactating mammary gland and non-secreting MECs, highlighting the importance of ZnT2 in general mammary gland biology. In this study, we used nulliparous and lactating ZnT2-null mice and characterized the consequences on mammary gland development, function during lactation and milk composition. We found that ZnT2 was primarily expressed in MECs and to a limited extent in macrophages in the nulliparous mammary gland and loss of ZnT2 impaired mammary expansion during development. Secondly, we found that lactating ZnT2-null mice had substantial defects in mammary gland architecture and MEC function during secretion, including fewer, condensed and disorganized alveoli, impaired Stat5 activation, and unpolarized MECs. Loss of ZnT2 led to reduced milk volume and milk containing less protein, fat and lactose compared with wild-type littermates, implicating ZnT2 in the regulation of mammary differentiation and optimal milk production during lactation. Together, these results demonstrate that ZnT2-mediated Zn transport is critical for mammary gland function, suggesting that defects in ZnT2 not only reduce milk Zn concentration but may compromise breast health and increase the risk for lactation insufficiency in lactating women.