The linkage between nutrition and cancer prevention is an intriguing concept that is gaining widespread support based on epidemiological and animal studies. Multiple mechanisms likely underlie dietary protection against cancer, with effects influenced by target tissue response, cell-cell interactions and developmental context. Given the negative correlation between breast cancer incidence and intake of soy foods by Asian women, and the increasing consumption of soy protein-based formula by infants in the Western world, we have studied soy protein isolate (SPI) used in most infant formula as a paradigm to evaluate diet as a risk factor in a rodent model of mammary cancer. We previously demonstrated that lifetime exposure to dietary SPI reduced the incidence of N-methyl-N-nitrosourea-induced mammary tumors in young adult rats relative to those fed the control diet Casein (CAS). This protection was associated with increased tumor suppressor PTEN and decreased Wnt signaling component expression in mammary epithelial cells at postnatal day (PND) 50 prior to carcinogen insult. To identify early events contributing to mammary tumor suppression by diet, we used Affymetrix RAE230A GeneChips containing 14280 probe sets and the GeneSpring Robust Multi-array program to analyze genomic profiles of mammary glands of prepubertal (PND21) rats lifetime exposed to SPI or CAS.
Early soy exposure via maternal diet regulates rat mammary epithelial differentiation by paracrine signaling from stromal adipocytes.
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View SamplesSenescent cells secrete a plethora of factors with potent paracrine signaling capacity. Strikingly, senescence, which acts as a defense against cell transformation, exerts pro-tumorigenic activities through its secretome by promoting numerous tumor-specific features, such as cellular proliferation, epithelial-mesenchymal transition and invasiveness. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has the unique activity of activating cell death exclusively in tumor cells. Given that the senescence-associated secretome supports cell transformation, we asked whether factor(s) of this secretome would establish a program required for the acquisition of TRAIL sensitivity. We found that conditioned media from several types of senescent cells (CMS) efficiently sensitized pre-transformed cells to TRAIL, while the same was not observed with normal or immortalized cells. Dynamic transcription profiling analysis of CMS-exposed pre-transformed cells revealed paracrine autoregulatory loop of senescence-associated secretome factors and a dominant role of CMS-induced MYC. Sensitization to TRAIL coincided with MYC upregulation and massive changes in gene regulation. CMS-induced MYC silenced its target gene CFLAR, encoding the apoptosis inhibitor FLIPL, thus leading to the acquisition of TRAIL sensitivity. Altogether, our results reveal that senescent cell-secreted factors exert a TRAIL sensitizing effect on pre-transformed cells by modulating the expression of MYC and CFLAR. Notably, CMS dose-dependent sensitization to TRAIL was observed with TRAIL-insensitive cancer cells and confirmed in co-culture experiments. Dissection and characterization of TRAIL-sensitizing CMS factors and the associated signaling pathway(s) may provide a mechanistic insight in the acquisition of TRAIL sensitivity and lead to novel concepts for the apoptogenic therapy of pre-malignant and TRAIL-resistant tumors.
Senescence-secreted factors activate Myc and sensitize pretransformed cells to TRAIL-induced apoptosis.
Cell line, Treatment, Time
View SamplesIn order to properly understand whether xenoestrogens act as estrogens, it is essential to possess a solid portrait of the physiological effects of exogenous estradiol. Because the estrogen-dependent gene expression is one of the primary biomarkers of estrogenic action, we have assessed effects of three doses of exogenous estradiol (0.1, 1.0 and 10 g/kg of body weight/day) on the mammary gland morphology and gene expression profiles by microarray analysis of prepubertal male and female rats of both sexes compared to untreated controls. Estradiol was administered subcutaneously with minipumps from weaning at PND21 to the end of the experiment at PND33. The data suggest that the male mammary is a sensitive tissue for estrogenicity assessment.
Mammary gland morphology and gene expression signature of weanling male and female rats following exposure to exogenous estradiol.
Sex
View SamplesStudies were undertaken to determine whether oscillatory behavior in the extracellular signal regulated kinase (ERK) pathway results in unique gene regulation patterns. Microarray analysis was performed on three subcloned populations of human keratinocytes with distinct ERK signaling/oscillation phenotypes.
ERK oscillation-dependent gene expression patterns and deregulation by stress response.
Specimen part
View SamplesMost commonly used models of non-alcoholic steatohepatitis (NASH) are diets based on specific gene knockouts or represent extreme manipulations of diet. We have examined the effects of modest increased caloric intake and high dietary unsaturated fat content on the development of NASH in male rats using a model in which overfeeding is accomplished via intragastric infusion of liquid diets as a part of total enteral nutrition. Male Sprague dawley rats were fed diets 5% corn oil containing diets at 187 Kcal/kg3/4/d or fed 70% corn oil containing diets at 220 Kcal/kg3/4/d for a period of 3 weeks. Hepatic gene expression were assessed at the end of the study. Our results indicate that overfeeding of high unsaturated fat diets leads to pathological, endocrine and metabolic changes characteristic of NASH patients and is associated with increased oxidative stress and TNF-a.
A new model for nonalcoholic steatohepatitis in the rat utilizing total enteral nutrition to overfeed a high-polyunsaturated fat diet.
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View SamplesCell body and pseudopod RNA are differentially regulated during the migration of the metastatic cancer cells.We wanted to identify the RNA which are upregulated in the pseudopodial (PS) fraction as compared to cell body fraction (CB).
Pseudopodial actin dynamics control epithelial-mesenchymal transition in metastatic cancer cells.
Cell line
View SamplesGenome wide gene expression analysis in G9a knockdown myoblasts
G9a promotes proliferation and inhibits cell cycle exit during myogenic differentiation.
Specimen part
View SamplesMaternal obesity during the pre-implantation period leads to a pro-inflammatory milieu in the ovaries. We conducted a global transcriptomic profiling in ovaries from TEN fed rats during the pre-implantation period. Microarray analysis revealed that obesity lead to increased expression of genes related to inflammation, decreased glucose transporters, and dysregulation of ovarian function-related genes in the ovaries. Our results suggest maternal obesity led to an up-regulation of inflammatory genes and Egr-1 protien expression in peri-implantation ovarian tissue, and a concurrent down-regulation of glucose transporters mRNA and AKT and PI3K protein levels.
Maternal obesity is associated with ovarian inflammation and upregulation of early growth response factor 1.
Sex, Specimen part
View SamplesAppropriate nutrition during early development is essential for optimal bone mass accretion; however, linkage between early nutrition, childhood bone mass and prevention of bone loss later in life has not been extensively studied. In this report, we have demonstrated several fundamental issues in the field. 1) A significant prevention of ovariectomy (OVX) -induced bone loss from adult rats can occur with only 14 days consumption of a blueberry-containing diet immediately prior to puberty. 2) The molecular mechanisms underlying these effects involve increased myosin production and preserved a shuttle for transcription factors such as Runx2 from cytoplasm to nucleolus which stimulates osteoblast differentiation and reduces mesenchymal stromal cell senescence. 3) The effects of blueberry diet on preserving fidelity of osteoblast differentiation also overcome reduced osteoblast differentiation and activity due to OVX-induced degradation of collagen matrix.
Feeding blueberry diets in early life prevent senescence of osteoblasts and bone loss in ovariectomized adult female rats.
Sex, Specimen part
View SamplesSoy foods have been suggested to have both positive health benefits and potentially adverse effects largely as a result of their content of isoflavone phytoestrogens. Since soy protein isolate (SPI) contains isoflavones, in addition to purported health benefits, safety concerns have been raised regarding the use of SPI and soy formulas, because of potential estrogenic actions during the neonatal period, including the potential for reproductive toxicity, infertility, and the possibility of increased risk for development and recurrence of estrogen sensitive cancers such as breast cancer. In the current study, we used a rat model to compare the effects of SPI with those of 17b-estradiol (E2), on global gene expression profiles and morphology in the female rat mammary gland. Rats were either fed AIN-93G diets containing casein (CAS) or SPI beginning on postnatal day (PND) 30.
Mammary gland morphology and gene expression differ in female rats treated with 17β-estradiol or fed soy protein isolate.
Sex
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