Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0596263 (carcinogenesis)
64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exogenous and dietary estrogens have been associated with modification of breast cancer risk. Mammary cancer model systems can be used to explore interactions between specific transgenes, and hormonal and dietary factors. Transgenic mice bearing the rat wild-type erbB-2 gene were used to study the effects of short-term hormonal exposure [17beta-estradiol (E2) or tamoxifen] or a soy meal diet on mammary carcinogenesis. In mice fed a casein diet, mammary tumors developed at an earlier age after short-term E2 exposure during the early reproductive period. The median mammary tumor latency was shortest (29 weeks) for the high-dose estrogen as compared with the lowest dose of E2 treated or placebo control mice (33 and 37 weeks, respectively). The timing of short-term E2 exposure was also important, with the most significant changes observed in mice exposed to E2 between 8 and 18 weeks of age. E2 exposure was associated with the subsequent development of more aggressive tumors as determined by histologic grade, multifocal tumor development, stromal invasion, and pulmonary metastasis. In contrast, short-term tamoxifen-exposed mice generally failed to develop mammary tumors by 60 weeks of age. Mice fed a soy meal diet developed mammary tumors at a later age than casein-fed animals treated with E2 or placebo, whereas no differences were observed by diet for the tamoxifen-treated mice. Mammary tumor prevention was >80% in tamoxifen-treated mice on either diet. Novel histologic tumor types were identified, suggesting greater phenotypic diversity than described previously. Benign mammary gland morphogenesis was also significantly altered by short-term hormonal exposure or dietary factors, consistent with the modification of mammary tumor risk in specific treatment groups. Estrogenic modulation of the mammary tumor phenotype in wild-type erbB-2 transgenic mice was observed. Histologic tumor types and clinical aggressivity not reported previously in this transgenic model were noted, suggesting greater biologic heterogeneity than reported previously. In addition, dietary phytoestrogens modified mammary development and tumor latency, suggesting a need for greater stringency in dietary assignment for transgenic mouse models of mammary neoplasia.
...
PMID:Hormonal and dietary modulation of mammary carcinogenesis in mouse mammary tumor virus-c-erbB-2 transgenic mice. 1275 Feb 62

In order to clarify the susceptibility of the Hras128 rat harboring copies of the human c-Ha-ras proto-oncogene to 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), Hras128 rats were intragastically treated with 100 mg/kg PhIP 8 times (females) or 80 mg/kg PhIP 10 times (males) over a 9-week period, then sacrificed at weeks 12 and 30. Multiple mammary tumors of adenocarcinoma type were induced in all females, while 83% of treated males developed adenocarcinomas, sarcomas and transitional carcinosarcomas, as evidenced by casein and vimentin immunoreactivity. All tumors examined had mutations in the c-Ha-ras transgene, while the endogenous rat c-Ha-ras gene was intact. Our results indicate that 1) Hras128 rats of both sexes are preferentially susceptible to mammary carcinogenesis with PhIP; 2) activation of the transgene, but not the endogenous c-Ha-ras gene, may be important in this regard; 3) the variety of tumor types evident in male rats indicates that immature mammary gland cells of the terminal end buds may be a target of PhIP; 4) although the transgene is expressed in all organs, susceptibility to PhIP is limited to mammary glands.
...
PMID:Preferential mammary carcinogenic effects of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in human c-Ha-ras proto-oncogene transgenic rats. 1513 66

Phenotypic and biological heterogeneity was studied in a single transgenic mouse model to determine the level of biological variance. We analyzed 1,258 tumors from 417 MMTV-wt-ErbB-2 transgenic mice, subdivided by casein or soy-based dietary randomization and hormonal treatment. Variance in tumor histologic features, growth pattern, invasion, metastases, and multi-focality were detected in untreated and treated mice. Ninety-three percent (1,174/1,258) of tumors had the solid growth pattern widely reported in this model. However, among the solid tumors, a spectrum of growth patterns, from well-circumscribed tumors with a pseudocapsule to locally invasive or highly aggressive, metastatic subtype, was observed. Of the non-solid tumors, glandular features were prominent in 84 (7%). Adenocarcinomas included papillary, acinar/glandular, and adenosquamous subtypes. Adenosquamous tumors were exclusively observed in the group of mice treated on a short-term basis with estrogen. In contrast to the reported literature for this transgenic mouse model, mammary tumors were multifocal in the majority of cases (303 of 417 mice, or 73%). Results of this extensive study of a single transgenic model of mammary tumorigenesis indicate phenotypic and biological heterogeneity not previously associated with this transgenic mouse. These data support a complex, multistep process of carcinogenesis and clonal evolution, with biological and phenotypic variance similar to that observed in human mammary cancer development.
...
PMID:Mammary tumor heterogeneity in wt-ErbB-2 transgenic mice. 1525 74

Protein kinase CK1, also known as casein kinase 1, participates in the phosphorylation of beta-catenin, which regulates the functioning of the Wnt signaling cascade involved in embryogenesis and carcinogenesis. beta-catenin phosphorylation occurs in a multiprotein complex assembled on the scaffold protein axin. The interaction of CK1alpha from Danio rerio with mouse-axin has been studied using a pull-down assay that uses fragments of axin fused to glutathione S transferase, which is bound to glutathione sepharose beads. The results indicate that the three lysines present in the basic region of residues 228-231 of CK1alpha are necessary for the binding of CK1 to axin. Lysine 231 is particularly important in this interaction. In order to define the relevance of the axin-CK1alpha interaction, the effect of the presence of axin on the phosphorylating activity of CK1alpha was tested. It is also evident that the region of axin downstream of residues 503-562 is required for CK1alpha interaction. The binding of CK1alpha to axin fragment 292-681 does not facilitate the phosphorylation of beta-catenin despite the fact that this axin fragment can also bind beta-catenin. Binding of CK1alpha to axin is not required for the phosphorylation of axin itself and, likewise, axin does not affect the kinetic parameters of the CK1alpha towards casein or a specific peptide substrate.
...
PMID:Basic region of residues 228-231 of protein kinase CK1alpha is involved in its interaction with axin: binding to axin does not affect the kinase activity. 1556 46

The isoflavone genistein (GEN), a biologically active component of soy foods, is associated with reduced breast cancer risk in women who consume soy-rich diets. GEN has been reported to influence many biological processes, of which suppression of cell proliferation and stimulation of apoptosis are considered to be the major pathways underlying its inhibition of tumorigenesis. This study evaluated the mechanism by which diets containing GEN promote mammary epithelial cell death. We report that mammary glands of young adult female rats exposed from gestation day 4 to postnatal day 50, to AIN-93G diets containing as sole protein source, casein (CAS) supplemented with GEN, or soy protein isolate (SPI+) had increased apoptosis, relative to rats fed CAS diet devoid of GEN. Mammary gland proliferation was unaffected by diet. The increased apoptotic index in mammary glands of GEN and SPI+ rats was accompanied by increased levels of the tumor suppressor protein PTEN (phosphatase and tensin homolog deleted in chromosome ten), albeit enhanced mammary expression of the pro-apoptotic p21, Bax and Bok genes was observed only in GEN-fed rats. GEN-induced apoptosis in MCF-7 cells was concomitant with increased PTEN expression, and this was abrogated by PTEN siRNA. MCF-7 cells treated with serum from GEN- or SPI(+)-fed rats had increased apoptosis as well as increased levels of the PTEN transcript. PTEN siRNA attenuated the increased apoptotic response of MCF-7 cells to serum from rats fed SPI+ or GEN, although the inhibition to basal (CAS serum) apoptotic levels was achieved only for cells treated with GEN serum. Decreased p21 and Bok gene expression accompanied the inhibition of apoptosis by PTEN siRNA. Data implicate PTEN in the induction of apoptosis by GEN and suggest that the promotion of apoptosis leading to inhibition of tumorigenesis in vivo by diets containing GEN may also involve the distinct activities of yet unknown GEN metabolite(s) and/or other systemic factors induced by GEN.
Carcinogenesis 2005 Oct
PMID:The soy isoflavone genistein promotes apoptosis in mammary epithelial cells by inducing the tumor suppressor PTEN. 1590 99

Breast cancer incidence is increased in women with both high and low birth weight. The latter is also associated with hyperglycaemia, insulin resistance and type-2 diabetes, each of which independently increases breast cancer risk. We showed previously in our model of poor early-growth that pregnancy estradiol levels were raised while offspring developed type-2 diabetes. We hypothesized that nutritionally-induced poor early-growth influences breast cancer risk and investigated this in our model. Wistar rat dams were given either a control diet (20% casein) or an isocaloric low-protein (LP) diet (8% casein) throughout pregnancy and lactation. Offspring postnatal mammary gland development was assessed by morphometry. To identify potential growth mechanisms, we measured protein expression of receptors involved in insulin and hormone signaling, both in cleared mammary gland lysates and isolated epithelial cells. Mammary tumor incidence and latency (n=96) was monitored after three weekly intraperitoneal nitrosomethylurea injections (50 mg/kg body wt). LP offspring displayed reduced postnatal ductal branching and epithelial invasion at 3 weeks, followed by compensatory mammary growth 1 week later coinciding with increased protein expression of receptors to insulin, IGF-1 and estrogen. Significantly, early-mammary tumor incidence (0-16 weeks post-treatment) was doubled in LP offspring [RR, 2.13 (1.02, 4.45); P=0.046]. The data suggest that poor early nutrition has an important influence on the mammary primordium, and increases future susceptibility to breast cancer. Up-regulated growth factor and hormone signaling during compensatory mammary growth may mediate this increased susceptibility and present potential targets for intervention.
Carcinogenesis 2007 Mar
PMID:Compensatory mammary growth following protein restriction during pregnancy and lactation increases early-onset mammary tumor incidence in rats. 1695 10

The mammary tumor-protective effects of dietary factors are considered to be mediated by multiple signaling pathways, consistent with the heterogeneous nature of the disease and the distinct genetic profiles of tumors arising from diverse mammary cell populations. In a 7,12-dimethylbenz(a)anthracene-induced model of carcinogenesis, we showed previously that female Sprague-Dawley rats exposed to AIN-93G diet containing whey protein hydrolysate (WPH) beginning at gestation Day 4 had reduced tumor incidence than those exposed to diet containing casein (CAS), due partly to increased mammary differentiation and reduced activity of phase I metabolic enzymes. Here, we evaluated the tumor-protective effects of these same dietary proteins to the direct-acting carcinogen N-methyl-N-nitrosourea (NMU). We found that lifetime exposure to WPH, relative to CAS, decreased mammary tumor incidence and prolonged the appearance of tumors in NMU-treated female rats, with no corresponding effects on tumor multiplicity. At 115 days post-NMU, histologically normal mammary glands from WPH-fed tumor-bearing rats had increased gene expression for the tumor suppressor BRCA1 and the differentiation marker kappa-casein than those of CAS-fed tumor-bearing rats. Tumor-bearing rats from the WPH group had more advanced tumors, with a greater incidence of invasive ductal carcinoma than ductal carcinoma in situ and higher serum C-peptide levels than corresponding rats fed CAS. WPH-fed tumor-bearing rats were also heavier after NMU administration than CAS tumor-bearing rats, although no correlation was noted between body weight and C-peptide levels for either diet group. Results demonstrate the context-dependent tumor-protective and tumor-promoting effects of WPH; provide support for distinct signaling pathways underlying dietary effects on development of mammary carcinoma; and raise provocative questions on the role of diet in altering the prognosis of existing breast tumors.
...
PMID:Tumor-protective and tumor-promoting actions of dietary whey proteins in an N-methyl-N-nitrosourea model of rat mammary carcinogenesis. 1704 72

Protein as well as starch is fermented in the colon, but the interaction between protein and starch fermentation and the impact on colonic oncogenesis is unknown. High-protein diets increase delivery of protein to the colon and might promote oncogenesis through generation of toxic products. We investigated the interaction of resistant starch (RS) with digestion-resistant potato protein (PP) on colonic fermentation events and their relationship to intestinal tumourigenesis. Male Sprague-Dawley rats were fed an AIN-76A-based diet for 4 weeks and intestinal neoplasms were induced by azoxymethane. Experimental diets included the following: no added RS or PP, 10% high amylose maize starch (source of RS) replacing digestible starch, 15% PP replacing casein and 10% high amylose maize starch+15% PP. Rats were maintained on diets until killed at 30 weeks. Feeding RS significantly increased short-chain fatty acid (SCFA) levels (P<0.001) in the caecum and colon. Importantly, butyrate concentration was significantly increased in the distal colon with RS (P<0.001). Feeding PP increased protein fermentation products, but this effect was reduced by adding RS to the diet. Intestinal neoplasms and colorectal adenocarcinomas were reduced by feeding RS (P<0.01) regardless of whether PP was fed, whereas PP alone increased the incidence and number of small intestinal neoplasms including the adenocarcinomas (P<0.01). In conclusion, RS altered the colonic luminal environment by increasing the concentration of SCFAs including butyrate and lowering production of potentially toxic protein fermentation products. These effects of RS not only protected against intestinal tumourigenesis but also ameliorated the tumour-enhancing effects of feeding indigestible protein.
Carcinogenesis 2007 Feb
PMID:Effect of dietary resistant starch and protein on colonic fermentation and intestinal tumourigenesis in rats. 1716 81

The linkage of nutrition and cancer prevention is an intriguing concept that is gaining widespread support. Here, we investigated the influence of developmental context on dietary protection against tumorigenesis initiated by the direct-acting carcinogen N-methyl-N-nitrosourea (NMU), and examined potential mechanisms underlying these effects. Rats were exposed only in utero or for lifetime to American Institute of Nutrition-93G diets made with casein (CAS), soy protein isolate (SPI) or CAS supplemented with genistein (GEN). Mammary glands of post-natal day (PND) 50 rats prior to NMU administration were examined for apoptotic status, pro-apoptotic gene expression and immunoreactive phosphatase and tensin homolog deleted on chromosome ten (PTEN) and epithelial cadherin (E-cadherin) levels, whereas mammary tumor parameters were evaluated 99 days post-NMU. Animals exposed only in utero to SPI had increased tumor latency, decreased tumor multiplicity and lower higher grade tumors, than those fed CAS. In utero exposure to GEN resulted in similar tumor parameters as the CAS group, whereas lifetime SPI exposure decreased tumor incidence that was not mimicked by in utero exposure alone. Mammary glands of PND50 rats fed lifetime SPI had increased terminal end bud apoptotic status and PTEN expression, than the other diet groups. Rats exposed only in utero to SPI or GEN had higher membrane E-cadherin in mammary structures than those lifetime-fed CAS or SPI. Thus, limited exposure during gestation to SPI can positively influence resistance to chemically induced mammary tumorigenesis later in life. Preventative strategies against mammary and other types of cancer might be uncovered by refinement of the developmental window for dietary factor exposure.
Carcinogenesis 2007 May
PMID:In utero exposure to maternal diets containing soy protein isolate, but not genistein alone, protects young adult rat offspring from NMU-induced mammary tumorigenesis. 1716 83

A role for the amount and type of dietary protein in the etiology of cancer has not been studied extensively. Nevertheless, there is no compelling evidence from epidemiological studies to indicate that protein, at levels usually consumed, is a risk factor for cancer. On the other hand, animal studies suggest that certain peptides and amino acids derived from dietary proteins may influence carcinogenesis. The predominant protein in milk, casein, its peptides, but not liberated amino acids, have antimutagenic properties. Animal models, usually for colon and mammary tumorigenesis, nearly always show that whey protein is superior to other dietary proteins for suppression of tumour development. This benefit is attributed to its high content of cystine/cysteine and gamma-glutamylcyst(e)ine dipeptides, which are efficient substrates for the synthesis of glutathione. Glutathione is an ubiquitous cellular antioxidant that directly or through its associated enzymes destroys reactive oxygen species, detoxifies carcinogens, maintains proteins in a reduced state and ensures a competent immune system. Various experiments showed that tumour prevention by dietary whey protein was accompanied by increased glutathione levels in serum and tissues as well as enhanced splenic lymphocyte proliferation, phagocytosis and natural killer, T helper and cytotoxic T cell activity. Whey protein components, beta-lactoglobulin, alpha-lactalbumin and serum albumin were studied infrequently, but results suggest they have anticancer potential. The minor component lactoferrin has received the most attention; it inhibits intestinal tumours and perhaps tumours at other sites. Lactoferrin acts by induction of apoptosis, inhibition of angiogenesis, modulation of carcinogen metabolising enzymes and perhaps acting as an iron scavenger. Supplementing cows with selenium increases the content of selenoproteins in milk, which on isolation inhibited colon tumorigenesis in rats.
...
PMID:A role for milk proteins and their peptides in cancer prevention. 1743 Jan 83


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---