Abstract
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.
Highlights
MicroRNAs are small, non-coding nucleic acid sequences (~22 bases) that regulate post-transcriptional gene expression by binding to a specific mRNA target and either inhibiting translation or promoting degradation[1]
Studies in mice and cultured mammary epithelial cell (MEC) show ZnT2 is redistributed from secretory vesicles to lysosomes in response to tumor necrosis factor α (TNFα), promoting lysosomal biogenesis and cell death, which are critical during early involution[16,17]
While we did find that sex-determining region Y-box 4 (SOX4) was significantly higher in women who harbored Exon[7] (p < 0.001), we found no difference in women who harbored T288S (p = 0.1), and SOX4 was significantly higher in women who harbored D103E (p < 0.0001) relative to women who harbored two normal ZnT2 alleles
Summary
MicroRNAs (miRNAs) are small, non-coding nucleic acid sequences (~22 bases) that regulate post-transcriptional gene expression by binding to a specific mRNA target and either inhibiting translation or promoting degradation[1]. Studies in vitro showed T288S is retained in the ER and lysosomes leading to zinc accumulation, ER and oxidative stress, and the activation of STAT3 signaling, a hallmark of mammary gland remodeling during involution[29] This provides compelling evidence that expression of genetic variants in ZnT2 may compromise breast function; the molecular pathways that underpin these consequences are not understood. We conducted a pilot study and used milk-derived miRNA profiling to identify molecular pathways affected in women harboring common non-synonymous genetic variants in ZnT2 in hopes of providing insight into the consequences on MEC function and lactation competence
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