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Metabolic vulnerability is a target of the antineoplastic effect of breastfeeding

ABSTRACT: Lactation is associated with a protective effect against breast and ovarian cancer, but the mechanism is unknown. Pappalysin-A (PAPP-A) is an extracellular protease normally expressed on the surface of placental trophoblasts during pregnancy but can also acts as an oncogene. We show that the serum of lactating mice or breastfeeding mothers protects against PAPP-A+ cancers specifically, while serum from virgin mice or parity-matched but non-lactating women do not. RNAseq revealed that lactating serum targets mitochondrial function in PAPP-A+ cancer cells leading to senescence. Further, we found that overexpression of PAPP-A in cancer cells is associated with lower mitochondrial function. These observations suggest that the anti-tumorigenic effect of lactation serum acts by exploiting the metabolic vulnerability of PAPP-A+ cancer cells. We identified corticotropin release hormone (CRH) using serum proteomics and show that CRF, the synthetic form of CRH, alone mimics the effect of lactating serum. Our study therefore identifies a mechanism of the protective effect of lactation against cancers and raises the possibility to use CRF as a therapeutic approach to mimic or enhance the protective effect of lactation for the prevention of breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE324012 | GEO | 2026/05/14

REPOSITORIES: GEO

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Project description:BACKGROUND: Lactation is extremely important for dairy cows; however, the understanding of the underlying metabolic mechanisms is very limited. This study was conducted to investigate the inherent metabolic patterns during lactation using the overall biofluid metabolomics and the metabolic differences from non-lactation periods, as determined using partial tissue-metabolomics. We analyzed the metabolomic profiles of four biofluids (rumen fluid, serum, milk and urine) and their relationships in six mid-lactation Holstein cows and compared their mammary gland (MG) metabolomic profiles with those of six non-lactating cows by using gas chromatography-time of flight/mass spectrometry. RESULTS: In total, 33 metabolites were shared among the four biofluids, and 274 metabolites were identified in the MG tissues. The sub-clusters of the hierarchical clustering analysis revealed that the rumen fluid and serum metabolomics profiles were grouped together and highly correlated but were separate from those for milk. Urine had the most different profile compared to the other three biofluids. Creatine was identified as the most different metabolite among the four biofluids (VIP=1.537). Five metabolic pathways, including gluconeogenesis, pyruvate metabolism, the tricarboxylic acid cycle (TCA cycle), glycerolipid metabolism, and aspartate metabolism, showed the most functional enrichment among the four biofluids (false discovery rate<0.05, fold enrichment >2). Clear discriminations were observed in the MG metabolomics profiles between the lactating and non-lactating cows, with 54 metabolites having a significantly higher abundance (P<0.05, VIP>1) in the lactation group. Lactobionic acid, citric acid, orotic acid and oxamide were extracted by the S-plot as potential biomarkers of the metabolic difference between lactation and non-lactation. The TCA cycle, glyoxylate and dicarboxylate metabolism, glutamate metabolism and glycine metabolism were determined to be pathways that were significantly impacted (P<0.01, impact value >0.1) in the lactation group. Among them, the TCA cycle was the most up-regulated pathway (P<0.0001), with 7 of the 10 related metabolites increased in the MG tissues of the lactating cows. CONCLUSIONS: The overall biofluid and MG tissue metabolic mechanisms in the lactating cows were interpreted in this study. Our findings are the first to provide an integrated insight and a better understanding of the metabolic mechanism of lactation, which is beneficial for developing regulated strategies to improve the metabolic status of lactating dairy cows.

Project description:Background: While the mechanisms underlying the lactation-induced adaptations of intermediary metabolism and immune response have been extensively studied in rodents and dairy cows, little is known in this regard in sows. Therefore, the present study aimed to explore the lactation-induced changes in hepatic gene expression in sows during lactation. Results: Using a porcine whole-genome microarray a total of 632 differentially expressed genes in the liver of lactating compared to non-lactating sows (each n = 10) could be identified. Enrichment analysis revealed that the differentially expressed genes were mainly involved in fatty acid metabolism, pyruvate metabolism, glutathione metabolism, glycine, serine and threonine metabolism, citrate cycle, glycerophospholipid metabolism, PPAR signaling, nitrogen metabolism, and focal adhesion. The most striking observation with respect to intermediary metabolism was that genes involved in fatty acid catabolism, the catabolism of gluconeogenic amino acids, the citrate cycle and the respiratory chain were up-regulated in the liver of sows during lactation. With respect to immune response, it could be demonstrated that genes encoding acute phase proteins and genes involved in tissue repair were up-regulated and genes encoding focal adhesion molecules were down-regulated in the liver of sows during lactation. Conclusion: The results from this study indicate that energy-generating pathways and pathways involved in the delivery of gluconeogenic substrates are induced in the liver of sows during lactation. The alterations of expression of genes encoding proteins involved in immune response suggest that lactation in sows may cause an adaptive immune response which possibly counteracts hepatic inflammation. For microarray analyses, four RNA pools each, for the non-lactating group (n = 4) and the lactating group (n = 4), were prepared from eight individual sows per group. To each RNA pool, RNA from two different sows per group contributed identical amounts of RNA.

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Metabolic vulnerability is a target of the antineoplastic effect of breastfeeding

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