| Increasing evidence from epidemiological findings and animal studies indicates that cancer risk in offspring can be reduced with increased maternal folate intake during pregnancy. On the other hand, low maternal intake of methyl nutrients increases the incidence of cancer in dams and offspring. However, the effects of fetal exposure to a maternal diet high in methyl nutrients on breast cancer are unknown, and data on the long term effects of such a diet are limited. Lipotropes are methyl group containing essential nutrients (methionine, choline, folate, and vitamin B12) which play key roles in one-carbon metabolism, a process that provides methyl groups for all biological methylation pathways. We investigated the effects of perinatal exposure and postnatal supplementation of lipotropes on the development and progression of breast cancer in female rat offspring. Pregnant Sprague-Dawley rats were fed control or methyl-supplemented diet during pregnancy or through lactation. The susceptibility of their female offspring to chemical carcinogenesis was determined using the nitrosomethylurea-induced rat cancer model. The offspring of dams fed lipotropes showed lower tumor incidence, tumor volume, and tumor numbers, and higher survival rate and tumor latency. Maternal lipotrope supplementation significantly reduced the levels of histone deacetylase 1 (HDAC1), methyl CpG binding protein 2 (MeCP2), and MDM2 mRNA in tumor tissues of the offspring. In a series of in vitro experiments, human breast cancer MCF-7 and T47D cells were cultured and treated with lipotropes and two chemotherapeutic drugs, doxorubicin and suberoylanilide hydroxamic acid (SAHA). Reduced cancer cell growth and increased expression of caspase-3 were seen in MCF-7 and T47D cells treated with lipotropes. Moreover, lipotropes increased the expression of genes associated with apoptosis and angiogenesis in MCF-7 cells. Lipotropes also showed additive cancer cell growth inhibition effects with doxorubicin and SAHA. Our findings demonstrate for the first time that maternal methyl diet reduces breast cancer risk of the offspring, and data reported herein may warrant further investigation regarding maternal methyl diet and offspring's breast cancer risk. |
