Milk-derived miRNA profiles elucidate molecular pathways that underlie breast dysfunction in women with common genetic variants in SLC30A2

Sci Rep. 2019 Sep 3;9(1):12686. doi: 10.1038/s41598-019-48987-4.


Studies in humans and pre-clinical animal models show milk-derived miRNAs reflect mammary gland function during lactation. The zinc transporter SLC30A2/ZnT2 plays a critical role in mammary gland function; ZnT2-null mice have profound defects in mammary epithelial cell (MEC) polarity and secretion, resulting in sub-optimal lactation. Non-synonymous genetic variation in SLC30A2 is common in humans, and several common ZnT2 variants are associated with changes in milk components that suggest breast dysfunction in women. To identify novel mechanisms through which dysfunction might occur, milk-derived miRNA profiles were characterized in women harboring three common genetic variants in SLC30A2 (D103E, T288S, and Exon 7). Expression of ten miRNAs differed between genotypes, and contributed to distinct spatial separation. Studies in breast milk and cultured MECs confirmed expression of ZnT2 variants alters abundance of protein levels of several predicted mRNA targets critical for breast function (PRLR, VAMP7, and SOX4). Moreover, bioinformatic analysis identified two novel gene networks that may underlie normal MEC function. Thus, we propose that genetic variation in genes critical for normal breast function such as SLC30A2 has important implications for lactation performance in women, and that milk-derived miRNAs can be used to identify novel mechanisms and for diagnostic potential.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Cation Transport Proteins / deficiency
  • Cation Transport Proteins / genetics*
  • Cation Transport Proteins / metabolism
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Female
  • Genotype
  • Humans
  • Mammary Glands, Animal / cytology
  • Mammary Glands, Animal / metabolism
  • Mice
  • Mice, Knockout
  • MicroRNAs / metabolism*
  • Milk, Human / metabolism*
  • Polymorphism, Genetic
  • Protein Interaction Maps / genetics
  • R-SNARE Proteins / genetics
  • R-SNARE Proteins / metabolism
  • SOXC Transcription Factors / genetics
  • SOXC Transcription Factors / metabolism
  • Young Adult


  • Cation Transport Proteins
  • MicroRNAs
  • R-SNARE Proteins
  • SLC30A2 protein, human
  • SOXC Transcription Factors
  • Sox4 protein, mouse
  • Sybl1 protein, mouse
  • Znt2 protein, mouse