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The Biology of Zinc Transport in Mammary Epithelial Cells: Implications for Mammary Gland Development, Lactation, and Involution

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Abstract

Zinc plays a critical role in a vast array of cellular functions including gene transcription, protein translation, cell proliferation, differentiation, bioenergetics, and programmed cell death. The mammary gland depends upon tight coordination of these processes during development and reproduction for optimal expansion, differentiation, and involution. For example, zinc is required for activation of matrix metalloproteinases, intracellular signaling cascades such as MAPK and PKC, and the activation of both mitochondrial-mediated apoptosis and lysosomal-mediated cell death. In addition to functional needs, during lactation the mammary gland must balance providing optimal zinc for cellular requirements with the need to secrete a substantial amount of zinc into milk to meet the requirements of the developing neonate. Finally, the mammary gland exhibits the most profound example of programmed cell death, which is driven by both apoptotic and lysosomal-mediated cell death. Two families of zinc-specific transporters regulate zinc delivery for these diverse functions. Members of the ZIP family of zinc transporters (ZIP1–14) import zinc into the cytoplasm from outside the cell or from subcellular organelles, while members of the ZnT family (ZnT1–10) export zinc from the cytoplasm. Recently, the ion channel transient receptor potential mucolipin 1 (TRPML1) has also been implicated in zinc transport. Herein, we review our current understanding of the molecular mechanisms through which mammary epithelial cells utilize zinc with a focus on the transport of zinc into discrete subcellular organelles for specific cellular functions during mammary gland development, lactation, and involution.

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Abbreviations

TRPML1:

Transient receptor potential mucolipin 1

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Acknowledgments

The authors thank Dr. Veronica Lopez and Vanessa Velasquez for technical assistance. This work was supported by R01HD058614, R01HD058614-S1, W82XWH-07-1-0692 and W81XWH-09-1-356 to SLK.

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Authors and Affiliations

  1. Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA, USA

    Nicholas H. McCormick, Stephen R. Hennigar & Shannon L. Kelleher

  2. Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA

    Kirill Kiselyov

  3. Department of Surgery, Penn State Hershey College of Medicine, Hershey, PA, USA

    Shannon L. Kelleher

  4. Department of Cell and Molecular Physiology, Penn State Hershey College of Medicine, Hershey, PA, USA

    Shannon L. Kelleher

  5. 222 Chandlee Laboratory, University Park, PA, 16802, USA

    Shannon L. Kelleher

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  1. Nicholas H. McCormick
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  2. Stephen R. Hennigar
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  3. Kirill Kiselyov
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  4. Shannon L. Kelleher
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Correspondence to Shannon L. Kelleher.

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McCormick, N.H., Hennigar, S.R., Kiselyov, K. et al. The Biology of Zinc Transport in Mammary Epithelial Cells: Implications for Mammary Gland Development, Lactation, and Involution. J Mammary Gland Biol Neoplasia 19, 59–71 (2014). https://doi.org/10.1007/s10911-013-9314-4

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  • DOI: https://doi.org/10.1007/s10911-013-9314-4

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