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Project description:BACKGROUND:While many studies have shown that maternal factors in pregnancy affect the cancer risk for offspring, few studies have investigated the impact of paternal exposures on their progeny's risk of this disease. Population studies generally show a U-shaped association between birthweight and breast cancer risk, with both high and low birthweight increasing the risk compared with average birthweight. Here, we investigated whether paternal malnutrition would modulate the birthweight and later breast cancer risk of daughters. METHODS:Male mice were fed AIN93G-based diets containing either 17.7% (control) or 8.9% (low-protein (LP)) energy from protein from 3 to 10 weeks of age. Males on either group were mated to females raised on a control diet. Female offspring from control and LP fathers were treated with 7,12-dimethylbenz[a]anthracene (DMBA) to initiate mammary carcinogenesis. Mature sperm from fathers and mammary tissue and tumors from female offspring were used for epigenetic and other molecular analyses. RESULTS:We found that paternal malnutrition reduces the birthweight of daughters and leads to epigenetic and metabolic reprogramming of their mammary tissue and tumors. Daughters of LP fathers have higher rates of mammary cancer, with tumors arising earlier and growing faster than in controls. The energy sensor, the AMP-activated protein kinase (AMPK) pathway, is suppressed in both mammary glands and tumors of LP daughters, with consequent activation of mammalian target of rapamycin (mTOR) signaling. Furthermore, LP mammary tumors show altered amino-acid metabolism with increased glutamine utilization. These changes are linked to alterations in noncoding RNAs regulating those pathways in mammary glands and tumors. Importantly, we detect alterations in some of the same microRNAs/target genes found in our animal model in breast tumors of women from populations where low birthweight is prevalent. CONCLUSIONS:Our study suggests that ancestral paternal malnutrition plays a role in programming offspring cancer risk and phenotype by likely providing a metabolic advantage to cancer cells.
| S-EPMC6117960 | biostudies-literature
Project description:We found that LP daughters have lower birthweight, alterations in mammary gland morphology and higher rates of mammary cancer. Further, we found that mammary glands and tumors of LP daughters are metabolic rewired, with alterations in the AMPK and amino-acid metabolism pathways. These changes were associated with differential expression of miRNAs 451a, miR-200c and miR-92a. Importantly, some of the same miRNAs and target genes alterations were detected in breast tumors of women from populations with high rates of low birthweight.
2018-06-14 | GSE114422 | GEO
Project description:We found that LP daughters have lower birthweight, alterations in mammary gland morphology and higher rates of mammary cancer. Further, we found that mammary glands and tumors of LP daughters are metabolic rewired, with alterations in the AMPK and amino-acid metabolism pathways. These changes were associated with differential expression of miRNAs 451a, miR-200c and miR-92a. Importantly, some of the same miRNAs and target genes alterations were detected in breast tumors of women from populations with high rates of low birthweight.
2018-06-14 | GSE114421 | GEO
Project description:Paternal malnutrition programs offspring’s breast cancer risk and tumor metabolism in a mouse model
| PRJNA471320 | ENA
Project description:Paternal malnutrition programs offspring’s breast cancer risk and tumor metabolism in a mouse model (MBD-seq)
| PRJNA471326 | ENA
Project description:Paternal malnutrition programs offspring’s breast cancer risk and tumor metabolism in a mouse model (small RNA-seq)
| PRJNA471323 | ENA
Project description:While many studies have shown that maternal weight and nutrition in pregnancy affects offspring's breast cancer risk, no studies have investigated the impact of paternal body weight on daughters' risk of this disease. Here, we show that diet-induced paternal overweight around the time of conception can epigenetically reprogram father's germ-line and modulate their daughters' birth weight and likelihood of developing breast cancer, using a mouse model. Increased body weight was associated with changes in the miRNA expression profile in paternal sperm. Daughters of overweight fathers had higher rates of carcinogen-induced mammary tumors which were associated with delayed mammary gland development and alterations in mammary miRNA expression. The hypoxia signaling pathway, targeted by miRNAs down-regulated in daughters of overweight fathers, was activated in their mammary tissues and tumors. This study provides evidence that paternal peri-conceptional body weight may affect daughters' mammary development and breast cancer risk and warrants further studies in other animal models and humans.
| S-EPMC4919621 | biostudies-literature
Project description:Regulators of chromatin structure and gene expression contribute to tumor formation and progression. The co-repressor CoREST1 regulates the localization and activity of associated histone modifying enzymes including lysine specific demethylase 1 (LSD1) and histone deacetylase 1 (HDAC1). Although several CoREST1 associated proteins have been reported to enhance breast cancer progression, the role of CoREST1 in breast cancer is currently unclear. Here we report that knockdown of CoREST1 in the basal-type breast cancer cell line, MDA-MB-231, led to significantly reduced incidence and diminished size of tumors compared to controls in mouse xenograft studies. Notably, CoREST1-depleted cells gave rise to tumors with a marked decrease in angiogenesis. CoREST1 knockdown led to a decrease in secreted angiogenic and inflammatory factors, and mRNA analysis suggests that CoREST1 promotes expression of genes related to angiogenesis and inflammation including VEGF-A and CCL2. CoREST1 knockdown decreased the ability of MDA-MB-231 conditioned media to promote endothelial cell tube formation and migration. Further, tumors derived from CoREST1-depleted cells had reduced macrophage infiltration and the secretome of CoREST1 knockdown cells was deficient in promoting macrophage migration and macrophage-mediated angiogenesis. Taken together, these findings reveal that the epigenetic regulator CoREST1 promotes tumorigenesis in a breast cancer model at least in part through regulation of gene expression patterns in tumor cells that have profound non-cell autonomous effects on endothelial and inflammatory cells in the tumor microenvironment.
| S-EPMC4368644 | biostudies-literature
Project description:BACKGROUND:Standard logistic regression with or without stepwise selection has the disadvantage of not incorporating model uncertainty and the dependency of estimates on the underlying model into the final inference. We explore the use of a Bayes Model Averaging approach as an alternative to analyze the influence of genetic variants, environmental effects and their interactions on disease. METHODS:Logistic regression with and without stepwise selection and Bayes Model Averaging were applied to a population-based case-control study exploring the association of genetic variants in tobacco smoke-related carcinogen pathways with breast cancer. RESULTS:Both regression and Bayes Model Averaging highlighted a significant effect of NAT1*10 on breast cancer, while regression analysis also suggested a significant effect for packyears and for the interaction of packyears and NAT2. CONCLUSIONS:Bayes Model Averaging allows incorporation of model uncertainty, helps reduce dimensionality and avoids the problem of multiple comparisons. It can be used to incorporate biological information, such as pathway data, into the analysis. As with all Bayesian analysis methods, careful consideration must be given to prior specification.
| S-EPMC2999590 | biostudies-literature
Project description:Significant evidence has indicated that tumor-associated macrophages (TAMs) play a critical role in the proliferation, invasion, angiogenesis, and metastasis of a variety of human carcinomas. In this study, we investigated whether near-infrared fluorescence (NIRF) imaging using a macrophage mannose receptor (MMR; CD206)-targeting agent could be used to noninvasively visualize and quantify changes in TAMs in vivo. The CD206-targeting NIRF agent, Dye-anti-CD206, was prepared and characterized in vitro and in vivo. By using NIRF imaging, we were able to noninvasively image tumor-infiltrating macrophages in the 4T1 mouse breast cancer model. Importantly, longitudinal NIRF imaging revealed the depletion of macrophages in response to zoledronic acid (ZA) treatment. However, ZA alone did not lead to the inhibition of 4T1 tumor growth. We therefore combined anti-macrophage ZA therapy and tumor cytotoxic docetaxel (DTX) therapy in the mouse model. The results demonstrated that this combination strategy could significantly inhibit tumor growth as well as tumor metastasis to the lungs. Based on these findings, we concluded that CD206-targeted molecular imaging can sensitively detect the dynamic changes in tumor-infiltrating macrophages, and that the combination of macrophage depletion and cytotoxic therapy is a promising strategy for the effective treatment of solid tumors.
| S-EPMC4377728 | biostudies-literature