P0328 - Expression of inflammation associated genes in the mammary gland of lactating women with elevated plasma triglycerides

Background: The benefits of breastfeeding are unparalleled. Unfortunately, obesity and diabetes are fueling a rise in the number of mothers who are physiologically unable to produce sufficient breast milk. Our aim was to identify gene expression signatures for mammary epithelial cells (MEC) during lactation that characterize insufficient breast milk production in obese women with elevated plasma triglycerides.

Methods: Fresh breastmilk samples were collected from 10 mothers with low milk production (0-254 mL/24h, LOW), and 8 control mothers with sufficient milk production (562-801 mL/24h, CON). All LOW mothers were obese and had elevated plasma triglycerides versus CON mothers (P<.05). We isolated total RNA from the cream layer of the breastmilk samples as a rich source of extracellular RNA of MEC origin. From the resulting transcriptomes, we intersected differentially expressed genes with KEGG inflammatory signaling pathways (cytokine-cytokine interactions, NF-κβ signaling, and Toll-like receptor signaling).

Results: Of 402 genes that were in the KEGG inflammatory pathways, 211 were expressed in lactating MEC. Thirty-three of these were differentially expressed (P<0.05), with 27 being upregulated (≥1.2-fold) and 6 downregulated (≤0.7-fold) in LOW versus CON transcriptomes. Differential expression included enrichment of proinflammatory genes (CXCL17, CX3CL1, CXCL16, CCL28, IL34, IL10RB, HVEM and FN14) and downregulation of anti-inflammatory genes (CSF1 and OPG).

Conclusions: Analysis of the MEC transcriptome provides a magnified snapshot of the delicate interplay of cellular networks, inflammatory signaling and immunoregulation in the lactating breast and its response to obesity. Upregulation of pro-apoptotic FN14, and downregulation of anti-apoptotic OPG, in association with upregulation of genes encoding chemokine proteins and their receptors, may compromise the viability of MEC during lactation. Defining the effects of obesity-induced inflammation on MEC function during lactation may enable the development of targeted interventions to improve human milk quantity and quality in affected women.