Human milk is a complex biological fluid that contains a wide variety of nutrients and bioactive components. A long-term focus of our research has been to understand the molecular role of the zinc transporter ZnT2 (SLC30A2) in regulating mammary gland function during lactation and involution and dysregulation in breast cancer, and how genetic variants in ZnT2 affect mammary cell function. These studies have been expanded to focus on identifying and understanding the functional consequences of additional gene variants on breast cell function, milk production and composition more broadly, and how these factors underlie low milk supply and poor breastfeeding outcomes. Additionally, we are currently interested in the potential of plant bioactives to improve milk production and quality, and developing novel storage solution to maintain the nutritional quality of human milk during storage.
Current research in the Kelleher Lab is broadly aimed at understanding the role of diet, genetics, and environmental contaminants on the regulation of mammary function and milk composition, and using this information to address common lactation problems. To do so, we use human milk as a “liquid biopsy” of the lactating mammary gland to identify non-invasive biomarkers of lactation disorders that affect milk production, secretion, and composition, and utilize functional genomics and cultured cells to understand the cellular mechanisms that effect the ability to produce enough high quality milk. Our goal is to develop evidence-based approaches to diagnose and treat lactation disorders empowering parents to meet their breastfeeding goals.
miRNAs as regulators of mammary gland function
Milk composition is partially programmed by both transcriptional and post-transcriptional changes in gene expression. miRNAs are small, non-coding RNAs that are potent post-transcriptional regulators of gene expression. They are produced by mammary cells and ~1,000 different miRNAs have been identified inhuman milk. Studies in dairy animals provide strong evidence that specific miRNAs are critical post-transcriptional regulators of key lactogenic pathways (apoptosis, cell cycle regulation, cellular growth, proliferation, and development and cell signaling (growth factor, immune, cytokine, and hormone). We recently determined that several miRNAs were associated with low milk supply in breastfeeding women, and propose that specific miRNAs are master regulators of lactation.
This project aims to understand the role of key miRNAs on the regulation of lactogenic mRNAs and cellular processes critical for lactogenesis II and regulating milk composition.
Plant bioactives and mammary epithelial cell function
For generations and across a diverse array of cultures, many women have used botanicals to increase their milk supply to support their breastfeeding goals. These approaches include consumption of specific herbs, foods, and supplements that contain bioactive polyphenols with purported galactagogue activity. Women frequently turn to botanicals because they are perceived as safe despite the lack of scientific data and regulation for biological and chemical standardization. Bioactives in fruit include a variety of polyphenols, which are plant metabolites thought to provide health benefits through a variety cell signaling pathways and antioxidation. Of note, numerous polyphenols and plant-based supplements (e.g., fenugreek, mulberry leaf, moringa, oatmeal, etc.) are purported increase milk supply in some women; however, little evidence supports these claims.
This project aims to understand effects of specific polyphenols on mammary epithelial cell function, enabling the development of diet-based approaches to improve milk production.
Development of novel diagnostic and predictive biomarkers of lactation
One long-term goal is to develop proprietary and cost-effective point-of-care platforms and clinical assays to diagnose and predict risk for lactation disorders in breastfeeding mothers. To do so, we use DNA sequencing, high-throughput SNP platforms, and a variety of unbiased ‘omics technologies to identify and validate biologically relevant biomolecules that are associated with milk supply and composition.
This project aims to identify molecules in milk that can be developed into novel non-invasive biomarkers of milk production and composition.
Genetic variation and mammary gland function
Mammary glands are highly specialized exocrine glands unique to mammals that have developed to produce milk to nourish the developing offspring. Extensive knowledge from studies in dairy animals indicates genetic differences inform lactation traits, such as milk yield and composition. Studies in breastfeeding women have begun to reveal that genetic variation in humans affects lactation traits as well. Genetic variants in SLC30A2 (ZnT2), FADS1/2, FUT2, NIS, and PRLR have been associated with milk volume and composition in humans, and we believe there are numerous other lactogenic variants to be discovered.
This project aims to identify novel genetic variants associated with milk composition and milk supply, and importantly, use functional genomics in cultured mammary epithelial cells to understand the biological consequences in breastfeeding women.
Improving milk stability during storage
Once human milk is pumped, milk quality begins to diminish as bacteria and immune cells, antibodies, and biologically active molecules such as enzymes degrade. Even when stored following current CDC guidelines, milk quality declines. Novel solutions to maintain the biological activity of human milk are needed to provide infants who are fed stored milk with the same nutritional and health benefits as infants fed directly from the breast.
This project aims to understand how milk components are affected by storage, and develop novel solutions to maintain the quality of human milk during storage.