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Organellar responses to lactation-induced stress impact the fate of post-partum mammary glands.

ABSTRACT: Breastfeeding protects against breast cancer, but not in all women and the mechanism remains elusive. Lactation implicates secretion of proteins through the endoplasmic reticulum (ER) and ER- mitochondria contacts for lipid metabolism. We show that in mice that share the same nuclear genome (BL/6) but differ in mitochondrial genomes (C57 or NZB) the outcome of lactation differs drastically. We analyzed the unfolded protein responses (UPR) of both organelles during lactation. In contrast to the BL/6C57mice, in BL/6NZB females, UPRs signaling is abruptly inhibited, no apoptosis is observed, post-partum hyperplasia develops and RNAseq demonstrates expression of pro-tumorigenic genes, which is consistent with increased post-partum tumor development. However, forced-induction of pro-apoptotic UPRER reverses this phenotype. Remarkably, milk fatty acids (FA) differ between genotypes and correlate with breast cancer risk in humans. These results indicate that mitochondrial genetics modulates organellar responses to lactation and its protective effect. Our results further raise the possibility of using milk FA-signature as a read-out of the underlying biology to predict risk of breast cancer in the future.

ORGANISM(S): Mus musculus

PROVIDER: GSE272881 | GEO | 2025/05/28

REPOSITORIES: GEO

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Idiosyncratic nature of lactation reveals link to breast cancer risk.

Project description:Breastfeeding protects against breast cancer in some women but not others, however the mechanism remains elusive. Lactation requires intense secretory activity of the endoplasmic reticulum (ER) for the production of milk proteins and ER- mitochondria contacts for lipid synthesis. We show that in female mice that share the same nuclear genome (BL/6) but differ in mitochondrial genomes (C57 or NZB), the biological processes engaged during lactation are entirely different at the sub-cellular organization and transcriptional levels resulting in anti-tumorigenic lactation in BL/6C57 females and pro-tumorigenic lactation in BL/6NZB females. Single cell sequencing identified a sub-population of cells, uniquely amplified during lactation in BL/6NZB females, which shares the genetic signature that characterizes post-partum breast cancer (PPBC) in humans relative to matched breast cancers in never pregnant women. Our data indicate that differences in ER and mitochondrial-stress responses during lactation between genotypes inadvertently leads to loss of p53 tumor suppressor function in BL/6NZB females allowing the expansion of the PPBC-like sub-population of cells. Overall, our data reveals the unexpected idiosyncratic nature of lactation and its impacts on the risk of the development of PPBC.

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Expression and differential expression analysis of milk samples from healthy and diseased diary cows.

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Gene expression of lipid metabolism-related genes correlated with milk fatty acids in dairy cows

Project description:The aim of the present study was to correlate lipid metabolism genes in the mammary gland tissue affected by stage of lactation and nutrition to the resulting milk fatty acids composition in grazing dairy cows, and to classify milk fatty acid (FA) groups based on variations in lipid metabolism gene expression patterns. Identifying the relationship between lipid metabolism genes in the mammary gland tissue and the resulting milk fatty acid composition is expected to greatly contribute to our understanding of milk fatty acid metabolism and to enhance opportunities to improve milk fat composition through nutrition. In fact, SNCA, SCD5, and PNPLA2 lipid metabolism-related genes affected by unsaturated fatty acids supplementation, were found to strongly correlated to different milk FA groups, but also contributed most to the classification of these FA groups, suggesting a significant role in mediating the lipid metabolism in the mammary gland tissue and determining the milk fatty acids composition. A total of 28 Holstein-Friesian dairy cows in mid-lactation were blocked according to parity (2.4 ± 0.63 years), days in milk (DIM; 153 ± 32.8 days), milk yield (25.7 ± 3.08 kg/d) and fat content (4.3 ± 0.12%). Cows were then randomly assigned to four UFA-sources based on rapeseed, soybean, linseed or a mixture of the three oils for 23 days (Period I) after which, all 28 cows were switched to a control diet for an additional 28 days (Period II). On the last day of both periods, mammary gland biopsies were taken to study genome-wide differences in lipid metabolism gene expression.

2011-01-01 | E-GEOD-20908 | biostudies-arrayexpress

Gene expression of lipid metabolism-related genes correlated with milk fatty acids in dairy cows

2011-01-01 | GSE20908 | GEO

Analysis of human breast milk cells: gene expression profiles during pregnancy, lactation, involution and mastitic infection.

Project description:The molecular processes underlying human milk production and the effects of mastitic infection are largely unknown because of limitations in obtaining tissue samples. Determination of gene expression in normal lactating women would be a significant step towards understanding why some women display poor lactation outcomes. Here we demonstrate the utility of RNA obtained directly from human milk cells to detect mammary epithelial cell (MEC)-specific gene expression. Milk cell RNA was collected from 5 time points (24 hours pre-partum during the colostrum period, mid lactation, two involution, and during a bout of mastitis) in addition to an involution series comprising three time points. Gene expression profiles were determined by use of human Affymetrix arrays. Milk cells collected during milk production showed that the most highly expressed genes were involved in milk synthesis (eg. CEL, OLAH, FOLR1, BTN1A1, ARG2), while milk cells collected during involution showed a significant down regulation of milk synthesis genes and activation of involution associated genes (eg. STAT3, NF-kB, IRF5, IRF7). Milk cells collected during mastitic infection revealed regulation of a unique set of genes specific to this disease state, whilst maintaining regulation of milk synthesis genes. Use of conventional epithelial cell markers was used to determine the population of MECâ??s within each sample. This paper is the first to describe the milk cell transcriptome across the human lactation cycle and during mastitic infection, providing valuable insight into gene expression of the human mammary gland. Human milk sampling throughout lactation cycle and during mastitic infection.

2016-04-01 | E-GEOD-77978 | biostudies-arrayexpress

Analysis of human breast milk cells: gene expression profiles during pregnancy, lactation, involution and mastitic infection.

Project description:The molecular processes underlying human milk production and the effects of mastitic infection are largely unknown because of limitations in obtaining tissue samples. Determination of gene expression in normal lactating women would be a significant step towards understanding why some women display poor lactation outcomes. Here we demonstrate the utility of RNA obtained directly from human milk cells to detect mammary epithelial cell (MEC)-specific gene expression. Milk cell RNA was collected from 5 time points (24 hours pre-partum during the colostrum period, mid lactation, two involution, and during a bout of mastitis) in addition to an involution series comprising three time points. Gene expression profiles were determined by use of human Affymetrix arrays. Milk cells collected during milk production showed that the most highly expressed genes were involved in milk synthesis (eg. CEL, OLAH, FOLR1, BTN1A1, ARG2), while milk cells collected during involution showed a significant down regulation of milk synthesis genes and activation of involution associated genes (eg. STAT3, NF-kB, IRF5, IRF7). Milk cells collected during mastitic infection revealed regulation of a unique set of genes specific to this disease state, whilst maintaining regulation of milk synthesis genes. Use of conventional epithelial cell markers was used to determine the population of MEC’s within each sample. This paper is the first to describe the milk cell transcriptome across the human lactation cycle and during mastitic infection, providing valuable insight into gene expression of the human mammary gland.

2016-04-01 | GSE77978 | GEO

Distinct mechanisms of non-autonomous UPRER mediated by GABAergic, glutamatergic, and octopaminergic neurons

Project description:The capacity to deal with stress declines during the aging process, and preservation of cellular stress responses is critical to healthy aging. The unfolded protein response of the endoplasmic reticulum (UPRER) is one such conserved mechanism which is critical for the maintenance of several major functions of the ER during stress, including protein folding and lipid metabolism. Hyperactivation of the UPRER by overexpression of the major transcription factor, xbp-1s, solely in neurons drives lifespan extension as neurons send a neurotransmitter-based signal to other tissue to activate UPRER in a non-autonomous fashion. Previous work identified serotonergic and dopaminergic neurons in this signaling paradigm. To further expand our understanding of the neural circuitry that underlies the non-autonomous signaling of ER stress, we activated UPRER solely in glutamatergic, octopaminergic, and GABAergic neurons in C. elegans and paired whole-body transcriptomic analysis with functional assays. We found that UPRER-induced signals from glutamatergic neurons increased expression of canonical protein homeostasis pathways and octopaminergic neurons promoted pathogen response pathways, while minor, but statistically significant changes were observed in lipid metabolism-related genes with GABAergic UPRER activation. These findings provide further evidence for the distinct role neuronal subtypes play in driving the diverse response to ER stress.

2024-06-15 | E-MTAB-14132 | biostudies-arrayexpress

16S rRNA gene amplification and maternal factors

Project description:Human breast milk contains a diverse community of bacteria but factors that produce variation in the breast milk microbiome are largely unknown. We evaluated if 1) maternal factors including breastfeeding practices modified the diversity and abundance of bacterial communities in breast milk and 2) if subclinical mastitis (SCM), an asymptomatic inflammatory condition occurring during lactation, induced a distinctive microbiota signature.

| EGAS00001003044 | EGA

Project description:Breast milk microbiota during lactation

| PRJNA495111 | ENA

Project description:Breast milk is the primary source of nutrition for newborns, and rich in immunological components. microRNAs (miRNAs), a well-defined group of non-coding small RNAs, are present in various body fluids (such as breast milk), which are selectively packaged inside the exosomes, a type of membrane vesicles, secreted by most cell types. These exosomal miRNAs could be actively delivered into recipient cells, and regulate target gene expression and recipient cell function. We present the lactation-related miRNA expression profiles in porcine milk exosomes across entire lactation period in pig industry (newborn to 28 days after birth) using deep sequencing technology. We found that the immune-related miRNAs are presented and enriched in breast milk exosomes, and generally resistant to relatively harsh conditions. Notably, these exosomal miRNAs exhibited the higher abundances in the colostrum (newborn to 3 days after birth) than that in the mature milk (7 to 28 days after birth), as well as in the serum of colostrum-feeding piglets compared with the only mature milk-feeding piglets. These immune-related miRNAs-loaded exosomes in breast milk may be transferred into the infant body via the digestive tract. These observations are prelude to the in-depth investigations of the essential roles of the breast milk in the development of the infant’s immune system. Eight small RNA libraries in porcine breast milk exosomes of six lactigenous stages (0, 3, 7, 14, 21 and 28 days after birth) from three female pigs were sequenced.

2012-09-17 | E-GEOD-36590 | biostudies-arrayexpress

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