title: Essential Role for Zinc Transporter 2 (ZnT2)-mediated Zinc Transport in Mammary Gland Development and Function during Lactation.
abstract: The zinc transporter ZnT2 (SLC30A2) imports zinc into vesicles in secreting mammary epithelial cells (MECs) and is critical for zinc efflux into milk during lactation. Recent studies show that ZnT2 also imports zinc 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 zinc transport is critical for mammary gland function, suggesting that defects in ZnT2 not only reduce milk zinc concentration but may compromise breast health and increase the risk for lactation insufficiency in lactating women.
authors: From the Interdisciplinary Graduate Physiology Program and Department of Nutritional Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, Departments of Cellular and Molecular Physiology.
authors: Sooyeon
authors: S
authors: Lee
authors: Department of Nutritional Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802.
authors: Stephen R
authors: SR
authors: Hennigar
authors: Departments of Cellular and Molecular Physiology, Surgery, Penn State Hershey College of Medicine, Hershey, Pennsylvania 17033.
authors: Samina
authors: S
authors: Alam
authors: Laboratory for Homeostatic Network, RCAI, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Yokohama 230-0045, Japan, and Laboratory of Immune Regulation, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka 513-8670, Japan.
authors: Keigo
authors: K
authors: Nishida
authors: From the Interdisciplinary Graduate Physiology Program and Department of Nutritional Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, Departments of Cellular and Molecular Physiology, Surgery, Penn State Hershey College of Medicine, Hershey, Pennsylvania 17033, Pharmacology, and slk39@psu.edu.
authors: Shannon L
authors: SL
authors: Kelleher
mesh_terms: D000818:Animals; D001692:Biological Transport; D015153:Blotting, Western; D027682:Cation Transport Proteins / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D007124:Immunoenzyme Techniques; D007774:Lactation / Q000502:physiology*; D008297:Male; D008321:Mammary Glands, Animal / Q000254:growth & development* / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008892:Milk / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; C543309:Znt2 protein, mouse; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D015032:Zinc
keywords: ZnT2; development; differentiation; lactation; mammary gland; secretion; zinc; zinc transporter