This study demonstrates that supplementation of lipotrope-fortified diet during puberty suppresses tumor growth, potentially through down-regulating Hdac1 and Dnmt1 gene expression. Our findings suggest that pubertal methyl diet plays an important role in the etiology of breast cancer, and further studies are warranted to develop preventative strategies against breast cancer.
The study determined whether feeding during lactation affects the suppressive effect of maternal dietary lipotropes (i.e., methionine, choline, folate, and vitamin B12) on mammary carcinogenesis. Pregnant Sprague-Dawley rats were randomly allocated to the control diet during pregnancy and lactation (CC), lipotropes-fortified diet during pregnancy (LC), lipotropes-fortified diet during pregnancy plus lactation (LL), or lipotropes-fortified diet during lactation (CL). Randomly selected female offspring from each group were injected intraperitoneally with 50 mg/kg body weight of N-nitroso-N-methylurea at 50 days of age to induce mammary tumors. The LC and LL diets significantly increased tumor latency and survival (P < 0.05). Tumor volumes were significantly suppressed in LC and LL offspring as compared with the CC and CL pups (3759.1 ± 563.0 and 3603.7 ± 526.1 vs. 7465.0 ± 941.1 and 5219.3 ± 759.8 mm(3), respectively; P < 0.05). Both LC and LL lowered tumor multiplicity as compared with CC and CL (P < 0.05). The LC and LL diets repressed transcription of histone deacetylase (HDAC) 1 as well as total HDAC enzyme activity as compared with CC and CL diets (P < 0.05). Data suggest that the tumor suppressive effect of maternal dietary lipotropes is primarily in utero and may be linked to regulation of proteins involved in chromatin remodeling.
Lipotropes are methyl group‐containing essential nutrients (i.e., methionine, choline, folic acid, and vitamin B12) that play key roles in one‐carbon metabolism. One‐carbon metabolism provides methyl groups for biological methylation pathways, including DNA methylation which controls the expression of genes. The objective of the study was to determine the extent to which maternal dietary lipotropes affect DNA methylation and the expression of genes in mammary glands of the offspring. Pregnant rats were fed either the control or lipotropes supplemented diet until parturition, at which point, rats were fed the control diet until weaning. At weaning, randomly selected female offspring from each group were kept on the control diet until they were bred for collection of the mammary tissues. Tissues were analyzed for global DNA methylation and gene expression. Maternal dietary lipotropes significantly increased DNA methylation in mammary tissues of the offspring [P=0.04]. Transcription of DNA methyltransferase 1 (Dnmt1) [P=0.01] and beta‐casein (Csn2) [P=0.01] genes was increased by maternal methyl diet. While, Dnmt1 is responsible for establishing and regulating methylation patterns, Csn2 is a marker for mammary cell differentiation. Thus, data may be informative to studies aimed at improving mammary development and lactation potential.
Grant Funding Source: NIH‐National Cancer Institute
The dynamic interactions of an individual matrix metalloproteinase-1 were imaged and monitored in the presence of either triple-helical or non-triple-helical, partially structured collagen-mimic substrates. The enzyme exhibited ten-fold increased catalytic turnover rates with the structurally modified substrate by skipping the triple-helix unwinding step during the catalytic pathway.
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