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Glycomics: Immunoglobulin G N-Glycosylation Associated with Mammary Gland Hyperplasia in Women.

ABSTRACT: Mammary gland hyperplasia (MGH) is very common, especially among young and middle-aged women. New diagnostics and biomarkers for MGH are needed for rational clinical management and precision medicine. We report, in this study, new findings using a glycomics approach, with a focus on immunoglobulin G (IgG) N-glycosylation. A cross-sectional study was conducted in a community-based population sample in Beijing, China. A total of 387 participants 40-65 years of age were enrolled in this study, including 194 women with MGH (cases) and 193 women who had no MGH (controls). IgG N-glycans were characterized in the serum by ultra-performance liquid chromatography. The levels of the glycan peaks (GPs) GP2, GP5, GP6, and GP7 were lower in the MGH group compared with the control group, whereas GP14 was significantly higher in the MGH group (p < 0.05). A predictive model using GP5, GP21, and age was established and a receiver operating characteristic curve analysis was performed. The sensitivity and specificity of the model for MGH was 61.3% and 63.2%, respectively, likely owing to receptor mechanisms and/or inflammation regulation. To the best of our knowledge, this is the first study reporting on an association between IgG N-glycosylation and MGH. We suggest person-to-person variations in IgG N-glycans and their combination with multiomics biomarker strategies offer a promising avenue to identify novel diagnostics and individuals at increased risk of MGH.

SUBMITTER: Meng Z

PROVIDER: S-EPMC7480711 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The physiology of the sow mammary gland is qualitatively well described and understood. However, the quantitative effect of various biological mechanisms contributing to the synthesis of colostrum and milk is lacking and more complicated to obtain. The objective of this study was to integrate physiological and empirical knowledge of the production of colostrum and milk in a dynamic model of a single sow mammary gland to understand and quantify parameters controlling mammary gland output. In 1983, Heather Neal and John Thornley published a model of the mammary gland in cattle, which was used as a starting point for the development of this model. The original cattle model was reparameterized, modified, and extended to describe the production of milk by the sow mammary gland during lactation and the prepartum production of colostrum as the combined output of immunoglobulins (Ig) and milk. Initially, the model was reparameterized to simulate milk synthesis potential of a single gland by considering biological characteristics and empirical estimations of sows and piglets. Secondly, the model was modified to simulate more accurately the responses to changes in milk removal rates. This was done by linking the ejectable milk storage capacity to the number of secretory cells rather than being constant throughout lactation. Finally, the model was extended to include the prepartum synthesis of milk and the kinetics of Ig into and out of the mammary gland. A progressive capacity of secretory cells to synthesize milk was used to differentiate the time between the onset of milk synthesis and Ig transfer. Changes in maximum milk removal rate, duration of milk ejection, and nursing interval exerted a great impact on the modeled milk output. Changes by ±60% in one of these parameters were capable of increasing milk output by 28% to 39% during the first 4 wk in lactation compared with the reference parameterization. This suggests that the ability of the piglet to remove milk from the gland exerts a key control on milk synthesis during lactation. Modeling colostrum as the combined output of Ig and milk allowed to represent the rapid decline in Ig concentration observed during the first hours after farrowing. In conclusion, biological and empirical knowledge was integrated into a model of the sow mammary gland and constitutes a simple approach to explore in which conditions and to what extent individual parameters influence Ig kinetics and milk production.

Project description:BackgroundAdvanced glycation end products (AGEs) are reactive metabolites intrinsically linked with modern dietary patterns. Processed foods, and those high in sugar, protein and fat, often contain high levels of AGEs. Increased AGE levels are associated with increased breast cancer risk, however their significance has been largely overlooked due to a lack of direct cause-and-effect relationship.MethodsTo address this knowledge gap, FVB/n mice were fed regular, low AGE, and high AGE diets from 3 weeks of age and mammary glands harvested during puberty (7 weeks) or adulthood (12 weeks and 7 months) to determine the effects upon mammary gland development. At endpoint mammary glands were harvested and assessed histologically (n ≥ 4). Immunohistochemistry and immunofluorescence were used to assess cellular proliferation and stromal fibroblast and macrophage recruitment. The Kruskal-Wallis test were used to compare continuous outcomes among groups. Mammary epithelial cell migration and invasion in response to AGE-mediated fibroblast activation was determined in two-compartment co-culture models. In vitro experiments were performed in triplicate. The nonparametric Wilcoxon rank sum test was used to compare differences between groups.ResultsHistological analysis revealed the high AGE diet delayed ductal elongation, increased primary branching, as well as increased terminal end bud number and size. The high AGE diet also led to increased recruitment and proliferation of stromal cells to abnormal structures that persisted into adulthood. Atypical hyperplasia was observed in the high AGE fed mice. Ex vivo fibroblasts from mice fed dietary-AGEs retain an activated phenotype and promoted epithelial migration and invasion of non-transformed immortalized and tumor-derived mammary epithelial cells. Mechanistically, we found that the receptor for AGE (RAGE) is required for AGE-mediated increases in epithelial cell migration and invasion.ConclusionsWe observed a disruption in mammary gland development when mice were fed a diet high in AGEs. Further, both epithelial and stromal cell populations were impacted by the high AGE diet in the mammary gland. Educational, interventional, and pharmacological strategies to reduce AGEs associated with diet may be viewed as novel disease preventive and/or therapeutic initiatives during puberty.

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Glycomics: Immunoglobulin G N-Glycosylation Associated with Mammary Gland Hyperplasia in Women.

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