Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The designation lobular neoplasia (LN) of the breast includes atypical lobular hyperplasia and lobular carcinoma in situ. Estrogen receptors (ER) play a significant role in breast carcinogenesis. In the present study, ER-alpha and ER-beta status are evaluated in 30 breast tissue specimens from patients whose main lesion was LN. A standard immunohistochemical procedure, using monoclonal antibodies for ER-alpha and ER-beta, was applied to the lesion and the adjacent normal breast tissues, the latter serving as control. In all cases, both receptors were expressed in LN as well as in normal breast ducts and lobules. Concerning ER-alpha, the Allred score and the percentage of ER-alpha-positive cells were significantly higher in LN than in the adjacent normal breast tissue. On the contrary, regarding ER-beta, the Allred score and the percentage of ER-beta-positive cells were significantly lower in LN compared with normal adjacent breast tissue. Greater increase in the percentage of ER-alpha-positive cells was associated with a smaller reduction in the percentage of ER-beta-positive cells and vice versa (Spearman's rho = -0.5044, p = 0.001). In conclusion, upregulation of ER-alpha and downregulation of ER-beta may represent two discrete molecular events in LN pathogenesis. Of notice, a mutually limiting interaction may exist between the two events.
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PMID:Immunohistochemical expression of estrogen receptors alpha and beta in lobular neoplasia. 1792 41

Androgens have long been known to be the major sex hormones that target the prostate during development, maturation, and carcinogenesis. It is now apparent that estrogens, both those synthesized by the body as well as those from our environment, also target the prostate during all stages of development. Little is known about the mechanisms involved in estrogen stimulation of carcinogenesis and less is known about how to prevent or treat prostate cancer through estrogenic pathways. To better understand how estrogens mediate their carcinogenic effects, the respective roles of estrogen receptor (ER)-alpha and ER-beta must be elucidated in the epithelial and stromal cells that constitute the prostate. Lastly, the significance of ER signaling during various ontogenic periods must be determined. Answers to these questions will further our understanding of the mechanisms of estrogen/ER signaling and will serve as a basis for chemopreventive and/or chemotherapeutic strategies for prostate cancer.
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PMID:Steroid hormones and carcinogenesis of the prostate: the role of estrogens. 1792 63

It was recently demonstrated that antiestrogens prevented prostate cancer (PRCA) in men. The source of estradiol (E2) that contributes to carcinogenesis, as well as the selected estrogen receptor (ER) signaling pathway, is unknown. To evaluate estrogen's effects in carcinogenesis, we developed a new model of PRCA utilizing testosterone and E2 to stimulate PRCA. To determine whether local in situ production of E2 affected incidence of PRCA, aromatase-knockout (ArKO) mice were evaluated. In contrast to the wild-type mice, ArKO mice had reduced incidences of PRCA, which implicates in situ production of E2 as an important determinant of PRCA. To determine whether E2-mediated responses were due to ER alpha or ER beta signaling, ER alpha-knockout (alphaERKO) or ERbeta-knockout (betaERKO) mice were used. Prostates from betaERKO mice underwent biochemical and histological carcinogenesis similar to wild-type mice, whereas prostates from alphaERKO mice remained free of pathology. These data suggest that effective prevention of carcinogenesis will require antagonism of ER alpha but not ER beta. This mouse model provides a means to examine genetic gain and loss of function and determine the efficacy of therapeutics on prostatic carcinogenesis.
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PMID:Prostatic hormonal carcinogenesis is mediated by in situ estrogen production and estrogen receptor alpha signaling. 1940 47

We have previously provided evidence showing an association between some precursor lesions with low nuclear grade breast carcinomas (LNGBCs). In this study, further immunophenotypic support to our proposed route of pathogenesis of LNGBC and their precursor lesions was provided. Precursor lesions including columnar cell lesions, atypical ductal hyperplasia, ductal carcinoma in situ, usual epithelial hyperplasia, and lobular neoplasia were compared with matching "morphologically normal" terminal lobular duct units and matching invasive carcinoma. The epithelial cells in the putative precursor flat epithelial atypia, atypical ductal hyperplasia, lobular neoplasia, ductal carcinoma in situ lesions, and their coexisting LNGBC were negative for basal and myoepithelial markers, but positive for CK19/18/8, estrogen receptor (ER)-alpha, Bcl-2, and cyclin D1. The ER-alpha/ER-beta expression ratio increased during carcinogenesis, as did expression of cyclin D1 and Bcl-2. p53 immunopositivity was found 3% in LNGBC versus 43% in high nuclear grade breast carcinoma (HNGBC), whereas ataxia telangiectasia mutated expression was absent or reduced in 22% of LNGBC versus 53% of HNGBC cases. In summary, our findings support the concept that flat epithelial atypia is the earliest morphologically identifiable nonobligate precursor lesion of LNGBC. These may represent a family of precursor, in situ and invasive neoplastic lesions belonging to the luminal "A" subclass of breast cancer. The balance between ER-alpha and ER-beta expression may be important in driving cyclin D-1 and Bcl-2 expression. Ataxia telangiectasia mutated may be one of the alternative regulatory mechanisms to TP53 mutation or dysfunction in low-grade and high-grade breast carcinoma. Our findings support the concept that progression of LNGBC to HNGBC (basal-like or HER2+) phenotype is an unlikely biologic phenomenon.
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PMID:Morphologic and molecular evolutionary pathways of low nuclear grade invasive breast cancers and their putative precursor lesions: further evidence to support the concept of low nuclear grade breast neoplasia family. 1822 78

Studies indicate that estrogen receptor beta, encoded by the ESR2 gene on chromosome 14q, may play a role in ovarian carcinogenesis. Using the genetic structure data generated by the Breast and Prostate Cohort Consortium (BPC3), we have comprehensively characterized the role of haplotype diversity in ESR2 and risk of ovarian cancer. Five haplotypes with a frequency of > or =5% were observed in White subjects and five haplotype tagging SNPs (htSNP) were selected to capture the locus diversity with a minimum R(h)(2) of 0.81. The htSNPs were genotyped in 574 White controls, 417 White invasive ovarian cancer cases, and 123 White borderline ovarian cancer cases from case-control studies carried out in Los Angeles County from 1994 through 2004. No statistically significant association was observed between the five htSNPs and related haplotypes and risk of ovarian cancer overall. Haplotype D was associated with a nonstatistically significant increased risk of invasive ovarian cancer overall (odds ratio, 1.38; 95% confidence interval, 0.93-2.02; P = 0.11) relative to the most common haplotype and a statistically significant increased risk of invasive clear cell ovarian cancer (odds ratio, 3.88; 95% confidence interval, 1.28-11.73; P = 0.016). Haplotype D was also reported by the BPC3 to be associated with increased risk of breast cancer. This haplotype warrants further investigation to rule out any effect with invasive ovarian cancer risk.
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PMID:Comprehensive evaluation of ESR2 variation and ovarian cancer risk. 1826 23

Pulmonary adenocarcinoma (PAC) is the leading type of lung cancer in smokers and non-smokers that arises in most cases from small airway epithelial cells. PAC has a high mortality due to its aggressive behavior and resistance to cancer therapeutics. We have shown previously that the proliferation of human PAC cells NCI-H322 and immortalized human small airway epithelial cells HPL1D is stimulated by cyclic adenosine monophosphate (cAMP)/protein kinase A-dependent phosphorylation of cyclic adenosine monophosphate response element-binding (CREB) protein and transactivation of the epidermal growth factor receptor and that this pathway is activated by beta-1-adrenoreceptors (beta(1)-ARs) and the non-genomic estrogen receptor beta. Our current in vitro studies with HPL1D and NCI-H322 cells showed that signaling via the gamma-amino butyric acid receptor (GABA(B)R) strongly inhibited base level and isoproterenol-induced cAMP, p-CREB, cyclic adenosine monophosphate response element-luciferase activity and p-extracellular regulated kinase-1 (ERK1)/2 and effectively blocked DNA synthesis and cell migration. The inhibitory effects of gamma-amino butyric acid (GABA) were disinhibited by the GABA(B)R antagonist CGP-35348 or GABA(B)R knockdown. Immunohistochemical investigation of hamster lungs showed significant underexpression of GABA in animals with small airway-derived PACs induced by the nicotine-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). These findings suggest that GABA may have tumor suppressor function in small airway epithelia and the PACs derived from them and that downregulation of GABA by NNK may contribute to the development of this cancer in smokers. Our findings suggest that marker-guided treatment with GABA or a GABA(B)R agonist of individuals with downregulated pulmonary GABA may provide a novel targeted approach for the prevention of PAC in smokers.
Carcinogenesis 2008 Oct
PMID:Gamma-aminobutyric acid, a potential tumor suppressor for small airway-derived lung adenocarcinoma. 1831 90

Colon cancer is the most frequent neoplasia of the intestine. This pathology is the third highest cause of death from cancer with 430,000 deaths globally per year. Estrogen has also been implicated in the development and progression of colon cancer. Also sex-specific differences have been suggested to be involved in the process. Previous studies have shown the estrogen beta receptor to be the dominant receptor type in normal colonic tissue and its down-regulation along with the progression of colorectal cancer. The presence of estrogen receptors and products of estrogen-related genes in the colon suggests that estrogens have direct effects on the colonic tissue. However, the specific effect of estrogens on a normal colon and the role in the colon carcinogenesis are far from clear. The aim of this study is to analyze by real-time polymerase chain reaction, the relative quantitative expression of the estrogen receptors beta, beta1, beta2, and beta5 in colon adenocarcinomas and to compare this expression with the respective in normal tissues. Moreover, we evaluate a possible correlation between estrogen's receptor expressions and disease stages. Normal tissues show estrogen receptor beta expression greater than pathologic tissues and the estrogen receptor beta result as most expressed in the lower disease stages.
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PMID:Expression of estrogen receptor beta in colon cancer progression. 1903 56

Breast cancer risk is highly modifiable by diet; however, mechanisms underlying dietary protection against mammary tumorigenesis remain poorly understood. A proportion of breast carcinomas is associated with deregulation of beta-catenin stability and amplification of c-Myc expression. We recently showed that dietary exposure to the soy isoflavone genistein (Gen) inhibited Wnt transduction in rat mammary epithelial cells in vivo. Here, we explored the role of Gen on cell adhesion protein, E-cadherin, expression to downregulate beta-catenin proto-oncogene function. In mammary glands of female rats exposed to dietary Gen, E-cadherin and beta-catenin protein levels were increased, concurrent with higher beta-casein gene expression. In HC11 mouse mammary epithelial cells, Gen diminished basal and Wnt-1-induced cell proliferation and attenuated Wnt-1 targets c-Myc and Cyclin D1 expression. Whereas, Gen had no effect on E-cadherin transcript levels, the abundance of membrane E-cadherin protein and of E-cadherin-beta-catenin adhesion complex was increased by Gen, attendant with downregulation of Wnt-1-induced free beta-catenin accumulation in cytosol. Gen inhibition of Wnt-induced c-Myc expression was mimicked by an estrogen receptor (ER)-beta-specific but not ER-alpha-specific agonist and was attenuated with loss of ER-beta expression, concordant with decreased E-cadherin expression. E-cadherin small-interfering RNA targeting eliminated Gen inhibition of Wnt-stimulated c-Myc expression and promoted Gen induction of basal c-Myc transcript levels and subsequent proliferation. Our studies identify E-cadherin as a Gen cellular target and demonstrate that the dichotomy in mammary epithelial response to Gen may be a function of cellular E-cadherin expression.
Carcinogenesis 2009 Feb
PMID:Soy isoflavone genistein upregulates epithelial adhesion molecule E-cadherin expression and attenuates beta-catenin signaling in mammary epithelial cells. 1907 77

The protective role of estrogens in the colon carcinogenesis has been suggested for many years and attributed mainly to estrogen receptor beta (ERbeta). However, the direct effect of estrogens and their action through ERbeta on the growth of colon cancer have been rarely studied. The aim of this study was to examine the effect of various concentrations (10(-4)-10(-12)M) of diarylpropionitrile (DPN)--a selective agonist of ERbeta--on the growth of murine MC38 colon cancer line. Moreover, the aim of this paper was the immunohistochemical assessment of estrogen and progesterone receptor expression in human colon tissues and in MC38 cells (only ERbeta). We found that DPN induced a growth inhibition of MC38 cancer (50-94% of control group) at the highest (10(-4)M) and two lowest concentrations (10(-11) and 10(-12)M). Furthermore, we detected a nuclear-cytoplasmic expression of ERbeta in human normal and neoplastic colon tissues and in the studied MC38 cancer cells. The inhibitory effect of DPN on the growth of MC38 colon cancer line suggests a possibility of using a selective estrogen receptor agonist in the treatment of colon cancer.
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PMID:The inhibitory effect of diarylpropionitrile, a selective agonist of estrogen receptor beta, on the growth of MC38 colon cancer line. 1910 Oct 81

Parabens is the name given to a group of p-hydroxybenzoic acid (PHBA) esters used in over 22,000 cosmetics as preservatives at concentrations up to 0.8% (mixtures of parabens) or up to 0.4% (single paraben). The group includes Methylparaben, Ethylparaben, Propylparaben, Isopropylparaben, Butylparaben, Isobutylparaben, and Benzylparaben. Industry estimates of the daily use of cosmetic products that may contain parabens were 17.76 g for adults and 378 mg for infants. Parabens in cosmetic formulations applied to skin penetrate the stratum corneum in inverse relation to the ester chain length. Carboxylesterases hydrolyze parabens in the skin. Parabens do not accumulate in the body. Serum concentrations of parabens, even after intravenous administration, quickly decline and remain low. Acute toxicity studies in animals indicate that parabens are not significantly toxic by various routes of administration. Subchronic and chronic oral studies indicate that parabens are practically nontoxic. Numerous genotoxicity studies, including Ames testing, dominant lethal assay, host-mediated assay, and cytogenic assays, indicate that the Parabens are generally nonmutagenic, although Ethylparaben and Methylparaben did increase chromosomal aberrations in a Chinese Hamster ovary cell assay. Ethylparaben, Propylparaben, and Butylparaben in the diet produced cell proliferation in the forestomach of rats, with the activity directly related to chain length of the alkyl chain, but Isobutylparaben and Butylparaben were noncarcinogenic in a mouse chronic feeding study. Methylparaben was noncarcinogenic when injected subcutaneously in mice or rats, or when administered intravaginally in rats, and was not cocarcinogenic when injected subcutaneously in mice. Propylparaben was noncarcinogenic in a study of transplacental carcinogenesis. Methylparaben was nonteratogenic in rabbits, rats, mice, and hamsters, and Ethylparaben was nonteratogenic in rats. Parabens, even at levels that produce maternal toxicity, do not produce fetal anomalies in animal studies. Parabens have been extensively studied to evaluate male reproductive toxicity. In one in vitro study, sperm were not viabile at concentrations as low as 6 mg/ml Methylparaben, 8 mg/ml Ethylparaben, 3 mg/ml Propylparaben, or 1 mg/ml Butylparaben, but an in vivo study of 0.1% or 1.0% Methylparaben or Ethylparaben in the diet of mice reported no spermatotoxic effects. Propylparaben did affect sperm counts at all levels from 0.01% to 1.0%. Epididymis and seminal vesicle weight decreases were reported in rats given a 1% oral Butylparaben dose; and decreased sperm number and motile activity in F(1) offspring of rats maternally exposed to 100 mg/kg day(- 1) were reported. Decreased sperm numbers and activity were reported in F(1) offspring of female rats given Butylparaben (in DMSO) by subcutaneous injection at 100 or 200 mg/kg day(- 1), but there were no abnormalities in the reproductive organs. Methylparaben was studied using rats at levels in the diet up to an estimated mean dose of 1141.1 mg/kg day(- 1) with no adverse testicular effects. Butylparaben was studied using rats at levels in the diet up to an estimated mean dose of 1087.6 mg/kg day(- 1) in a repeat of the study noted above, but using a larger number of animals and a staging analysis of testicular effects-no adverse reproductive effects were found. Butylparaben does bind to estrogen receptors in isolated rat uteri, but with an affinity orders of magnitude less than natural estradiol. Relative binding (diethylstilbesterol binding affinity set at 100) to the human estrogen receptors alpha and beta increases as a function of chain length from not detectable for Methylparaben to 0.267 +/- 0.027 for human estrogen receptor alpha and 0.340 +/- 0.031 for human estrogen receptor beta for Isobutylparaben. In a study of androgen receptor binding, Propylparaben exhibited weak competitive binding, but Methylparaben had no binding effect at all. PHBA at 5 mg/kg day(-1) subcutaneously (s.c.) was reported to produce an estrogenic response in one uterotrophic assay using mice, but there was no response in another study using rats (s.c. up to 5 mg/kg day(- 1)) and mice (s.c. up to 100 mg/kg day(- 1)) and in a study using rats (s.c. up to 100 mg/kg day(- 1)). Methylparaben failed to produce any effect in uterotrophic assays in two laboratories, but did produce an effect in other studies from another laboratory. The potency of Methylparaben was at least 1000x less when compared to natural estradiol. The same pattern was reported for Ethylparaben, Propylparaben, and Butylparaben when potency was compared to natural estradiol. In two studies, Isobutylparaben did produce an estrogenic response in the uterotrophic assay, but the potency was at least 240,000x less than estradiol. In one study, Benzylparaben produced an estrogenic response in the uterotrophic assay, but the potency was at least 330,000x less than estradiol. Estrogenic activity of parabens and PHBA was increased in human breast cancer cells in vitro, but the increases were around 4 orders of magnitude less than that produced by estradiol. Parabens are practically nonirritating and nonsensitizing in the population with normal skin. Paraben sensitization has occurred and continues to be reported in the case literature, but principally when exposure involves damaged or broken skin. Even when patients with chronic dermatitis are patch-tested to a parabens mix, parabens generally induce sensitization in less than 4% of such individuals. Many patients sensitized to paraben-containing medications can wear cosmetics containing these ingredients with no adverse effects. Clinical patch testing data available over the past 20 years demonstrate no significant change in the overall portion of dermatitis patients that test positive for parabens. As reviewed by the Cosmetic Ingredient Review (CIR) Expert Panel, the available acute, subchronic, and chronic toxicity tests, using a range of exposure routes, demonstrate a low order of parabens' toxicity at concentrations that would be used in cosmetics. Parabens are rarely irritating or sensitizing to normal human skin at concentrations used in cosmetics. Although parabens do penetrate the stratum corneum, metabolism of parabens takes place within viable skin, which is likely to result in only 1% unmetabolized parabens available for absorption into the body. The Expert Panel did consider data in the category of endocrine disruption, including male reproductive toxicity and various estrogenic activity studies. The CIR Expert Panel compared exposures to parabens resulting from use of cosmetic products to a no observed adverse effect level (NOAEL) of 1000 mg/kg day(- 1) based on the most statistically powerful and well-conducted study of the effects of Butylparabens on the male reproductive system. The CIR Expert Panel considered exposures to cosmetic products containing a single parabens preservative (use level of 0.4%) separately from products containing multiple parabens (use level of 0.8%) and infant exposures separately from adult exposures in determining margins of safety (MOS). The MOS for infants ranged from approximately 6000 for single paraben products to approximately 3000 for multiple paraben products. The MOS for adults ranged from 1690 for single paraben products to 840 for multiple paraben products. The Expert Panel considers that these MOS determinations are conservative and likely represent an overestimate of the possibility of an adverse effect (e.g., use concentrations may be lower, penetration may be less) and support the safety of cosmetic products in which parabens preservatives are used.
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PMID:Final amended report on the safety assessment of Methylparaben, Ethylparaben, Propylparaben, Isopropylparaben, Butylparaben, Isobutylparaben, and Benzylparaben as used in cosmetic products. 1910 32


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