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)

Our recent studies have shown that overexpression of aromatase results in increased tissue estrogenic activity and induction of hyperplastic and dysplastic lesions in female mammary glands and gynecomastia and testicular cancer in male aromatase transgenic mice. Both aromatase mRNA and protein are overexpressed in transgenic mammary glands and its expression is not limited to epithelial cells. However, it is more in epithelial than in stromal cells. Our results also indicate aromatase overexpression-induced changes in mammary glands can be abrogated with very low concentrations of the aromatase inhibitor, letrozole. Low concentration of letrozole had no effect on normal physiology as indicated by no significant change in the circulating levels of estradiol and follicle stimulating hormone as well as no change in estrogen responsive genes such as the progesterone receptor and lactoferrin in the uterine tissue. These observations indicate that the expression of aromatase in both epithelial and stromal cells can influence the complex interactions of biochemical pathways leading to mammary carcinogenesis and that the aromatase inhibitor, letrozole can be used as chemopreventive agents without affecting normal physiology.
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PMID:Aromatase overexpression transgenic mice model: cell type specific expression and use of letrozole to abrogate mammary hyperplasia without affecting normal physiology. 1185 Feb 4

The tumour suppressor gene TP53 and its downstream effector p21 are thought to play major roles in the development of breast cancer. We investigated three common sequence variants in TP53 and p21 for possible associations with the risk of breast cancer and with various phenotypic features of this disease. A total of 351 cases were available for study. Germline DNA obtained from female subjects of similar age but without cancer was used to estimate the TP53 and p21 genotype frequencies in a control population. A single nucleotide polymorphism in intron 2 of p21 was associated with slightly increased breast cancer risk (RR = 1.4, P = 0.011) and with well/moderately differentiated tumour histology (P = 0.029). The 16 bp insertion polymorphism in intron 3 of TP53 was associated with poor histological grade (OR = 2.3, P = 0.013) independently of other pathological features. The codon 31 polymorphism in p21 was strongly linked to negative progesterone receptor status (OR = 3.4, P = 0.0001), suggesting this variant may have functional significance for the progesterone signalling pathway in breast cancer. These results add to the growing body of evidence that genetic variants can influence not only the risk of breast cancer but also the disease phenotype.
Carcinogenesis 2002 Feb
PMID:Associations between common polymorphisms in TP53 and p21WAF1/Cip1 and phenotypic features of breast cancer. 1187 38

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous pollutant and promoter of carcinogenesis. This study investigated the interaction between TCDD and different estrogens in a cancer cell line (ID8) derived from mouse ovarian epithelium. TCDD-induced ethoxyresorufin-O-deethylase (EROD) activity and cytochrome P4501A1 (CYP1A1) expression in a dose- and time-dependent manner. Estrogen receptor (ER) alpha mRNAs were constitutively expressed, but ER beta and progesterone receptor (PR) mRNAs were not expressed. Induction of EROD by TCDD was completely inhibited by a alpha-naphthoflavone and phenanthroline, two aryl hydrocarbon receptor (AhR) antagonists. Progesterone and gonadotropins (FSH and LH) had no effect on the induction of EROD by TCDD. Congeners of 17beta-estradiol (E2) increased the induction of EROD activity by TCDD dose-dependently in the relative potency order: estrone (El)>E2> or = 4-hydroxyestradiol (4OHE2)> or = 2-hydroxyestradiol (2OHE2). In contrast, estriol (E3) decreased EROD activity induced by TCDD. E2 increased TCDD-induced CYP1A1 protein and mRNA whereas E3 decreased both the protein and mRNA. E2 did not alter luciferase activity induced by TCDD in cells transfected with a luciferase reporter containing dioxin response elements (DRE) or a CYP1A1 promoter. In contrast, E3 dose-dependently decreased the luciferase activity. A pure anti-estrogen (ICI 182780) inhibited the interaction between E2 and TCDD but did not block E3's effect on EROD activity. These results indicate that E2 may affect TCDD-induced CYP1A1 expression by a mechanism different from E3 in ID8 cells. It appears that the potentiation of E2 in the induction of CYP1A1 by TCDD occurs by a mechanism involving ER alpha since a specific ER antagonist blocked the potentiation. The inhibitory effect of E3 may be due to a rapid direct effect on EROD and a later suppression of CYP1A1 expression.
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PMID:Estradiol enhances and estriol inhibits the expression of CYP1A1 induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in a mouse ovarian cancer cell line. 1209 19

A diet high in soy is associated with many health benefits, including reduced incidence of breast cancer. The soy phytoestrogen, genistein, is hypothesized to contribute to mammary chemoprevention via interaction with estrogen receptors (ERs) alpha and/or beta. These steroid signaling pathways are believed to exert control over proliferation and differentiation of the mammary gland by a complex bidirectional interaction with the epidermal growth factor (EGF) signaling pathway. The current work was designed to study the role of these two pathways in prepubertal mammary gland growth. Female Sprague-Dawley CD rats were injected with genistein (500 micro g/g body wt) or estradiol benzoate (EB) (500 ng/g body wt) on days 16, 18 and 20. Whole mount analysis of mammary glands from 21-day-old rats showed that both treatments resulted in significantly increased terminal end buds (TEBs), and increased ductal branching, compared with animals given the vehicle, dimethylsulfoxide (DMSO). Both effects were inhibited by blockage of ER function by pre-treating with 2 mg ICI 182,780/kg body wt, a steroidal anti-estrogen. Immunoblotting analyis of mammary gland extracts demonstrated increased epidermal growth factor receptor (EGFR) and progesterone receptor (PR) expression following treatment with EB or genistein. Tyrosine-phosphorylated EGFR, as measured by immunoprecipitation/immunoblotting was also increased, but when normalized to total receptors, there was no net effect. The expression and phosphorylation of downstream targets of the EGFR, mitogen activating kinase kinase (MEK 1 and 2) and extracellular signal regulated kinases 1 and 2 (ERK 1 and 2) were not significantly affected. Anti-estrogen pre-treatment prevented the increase in EGFR, phospho-EGFR and PR. The data indicate an ER-based mechanism of action for genistein in mammary gland proliferation and differentiation, which can lead to protection against mammary cancer.
Carcinogenesis 2002 Sep
PMID:Genistein action in the prepubertal mammary gland in a chemoprevention model. 1218 89

We tested the hypothesis that adolescent dietary vitamin A intake impacts mammary gland development and subsequent sensitivity to carcinogenesis. Sprague-Dawley rats were fed a purified diet that was vitamin A deficient, adequate (2.2 mg retinyl palmitate/kg diet), or supranutritional (16 mg retinyl palmitate/kg diet) from 21 to 63 days of age, the period of adolescent mammary gland development. At 73 days of age, rats were given 1-methyl-1-nitrosourea (25 mg/kg body wt i.p.) and monitored for mammary tumors. Tumors appeared earlier and more frequently in rats fed vitamin A-deficient or -supplemented diets. Vitamin A deficiency during adolescence was associated with alveolar mammary gland development and precocious milk protein expression, while supplementation was associated with ductal gland development and suppression of milk protein expression. Differences in circulating estradiol and mammary gland estrogen receptor-alpha, and estrogen-responsive progesterone receptor mRNA were not observed, suggesting that the effects of vitamin A on mammary gland development and carcinogenesis are estrogen independent. Mammary expression of another hormone receptor that regulates milk protein expression, the glucocorticoid receptor, was also unaffected. These results demonstrate that vitamin A intake during adolescence alters mammary gland differentiation and indicate that a narrow range of vitamin A intake during adolescence protects against carcinogenesis.
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PMID:Adolescent vitamin A intake alters susceptibility to mammary carcinogenesis in the Sprague-Dawley rat. 1223 54

Cyr61 is a secreted pro-angiogenic factor that belongs to an emerging family of growth regulators classified as CCN (CTGF/Cyr61/NOV). Work in our laboratory has focused on sex steroid regulation of Cyr61 and its role in hormonal carcinogenesis. In this study, both Cyr61 mRNA and protein were induced by the progestin, R5020, in T47D mammary adenocarcinoma cells in a dose- and time-dependent fashion. Cyr61 gene induction by R5020 was transcriptionally regulated by progesterone receptor (PR) as the antiprogestin, RU486, and actinomycin D blocked induction completely. Moreover, Cyr61 was upregulated by epidermal growth factor (EGF) but not by R5020 in the PR-MDA-MB-431 mammary adenocarcinoma cell line, underscoring the necessity of PR. The functional significance of progestin induction of Cyr61 in breast cancer cell growth was demonstrated by anti-Cyr61 neutralizing antibodies, which diminished R5020 and EGF-dependent DNA synthesis by 30%. Moreover, anti-Cyr61 neutralizing antibodies reduced the synergistic effects of R5020 and EGF on T47D cell growth by 30%. Accordingly, protein lysates generated from stage II invasive ductal carcinomas (n = 20) were analyzed in order to determine the relevance of Cyr61 expression in the context of breast tumorigenesis. Remarkably, increased Cyr61 protein expression was observed in greater than 50% of primary breast tumor lysates that were progesterone receptor (PR)+ but estrogen receptor negative. Taken together, our data suggest that in addition to its proangiogenic activity, Cyr61 may be a novel mediator of progesterone activity in enhancing growth-factor-driven tumor growth in breast cancer.
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PMID:The angiogenic factor Cyr61 is induced by the progestin R5020 and is necessary for mammary adenocarcinoma cell growth. 1237 62

The identification of a second oestrogen receptor, oestrogen receptor (ER) beta, has led to a need to assess the relative importance of the classical ERalpha and ERbeta in human breast and breast carcinomas. ERalpha and ERbeta mRNA was assessed in 61 carcinomas, 8 benign breast lesions, and 30 samples of normal breast using reverse transcriptase (RT)-nested polymerase chain reaction (PCR). Immunohistochemical analysis of ERalpha and ERbeta was performed in 62 carcinomas, the 38 non-malignant breast tissues, and 32 normal breast samples with menstrual cycle data. ERalpha mRNA was detected in 92% of breast cancers, with ERbeta mRNA (wild-type and/or variant form) in 85%; 72% had ERalpha protein, 62% progesterone receptor (PgR), and 32% ERbeta. ERalpha protein had a strong correlation with grade; ERbeta did not, although it was present in three of four grade I carcinomas and in special types. There was no correlation between the presence of ERalpha and ERbeta protein. In non-malignant breast, similar expression of ERalpha and beta was observed, apart from expression of ERbeta in stromal cells and myoepithelium, the latter being confirmed by RT-PCR and western blotting. There were differences in ERalpha in relation to the menstrual cycle but not PgR or ERbeta. The findings indicate a need to understand the role and regulation of ERbeta in normal breast and the reason for its down-regulation in mammary carcinogenesis.
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PMID:Oestrogen receptors alpha and beta differ in normal human breast and breast carcinomas. 1243 14

The present study addresses the capacity of heregulin (HRG), a ligand of type I receptor tyrosine kinases, to transactivate the progesterone receptor (PR). For this purpose, we studied, on the one hand, an experimental model of hormonal carcinogenesis in which the synthetic progestin medroxyprogesterone acetate (MPA) induced mammary adenocarcinomas in female BALB/c mice and, on the other hand, the human breast cancer cell line T47D. HRG was able to exquisitely regulate biochemical attributes of PR in a way that mimicked PR activation by progestins. Thus, HRG treatment of primary cultures of epithelial cells of the progestin-dependent C4HD murine mammary tumor line and of T47D cells induced a decrease of protein levels of PRA and -B isoforms and the downregulation of progesterone-binding sites. HRG also promoted a significant increase in the percentage of PR localized in the nucleus in both cell types. DNA mobility shift assay revealed that HRG was able to induce PR binding to a progesterone response element (PRE) in C4HD and T47D cells. Transient transfections of C4HD and T47D cells with a plasmid containing a PRE upstream of a chloramphenicol acetyltransferase (CAT) gene demonstrated that HRG promoted a significant increase in CAT activity. In order to assess the molecular mechanisms underlying PR transactivation by HRG, we blocked ErbB-2 expression in C4HD and T47D cells by using antisense oligodeoxynucleotides to ErbB-2 mRNA, which resulted in the abolishment of HRG's capacity to induce PR binding to a PRE, as well as CAT activity in the transient-transfection assays. Although the inhibition of HRG binding to ErbB-3 by an anti-ErbB-3 monoclonal antibody suppressed HRG-induced PR activation, the abolishment of HRG binding to ErbB-4 had no effect on HRG activation of PR. To investigate the role of mitogen-activated protein kinases (MAPKs), we used the selective MEK1/MAPK inhibitor PD98059. Blockage of MAPK activation resulted in complete abrogation of HRG's capacity to induce PR binding to a PRE, as well as CAT activity. Finally, we demonstrate here for the first time that HRG-activated MAPK can phosphorylate both human and mouse PR in vitro.
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PMID:Heregulin induces transcriptional activation of the progesterone receptor by a mechanism that requires functional ErbB-2 and mitogen-activated protein kinase activation in breast cancer cells. 1252 13

Steroids and their nuclear receptors play crucial roles in the development and maintenance of normal functions of the human mammary gland (HMG). They have also been implicated in breast carcinogenesis. However, the study of steroid action in normal HMG has been hampered by experimental difficulties. By using a newly established in vitro long-term culture method, we successfully cultured normal HMG tissue for more than 2 months without detriment to its morphology or steroid receptor expression. Expression of the cellular structural and extracellular matrix proteins was similar to that prior to culture, and HMG tissue retained its properties of steroid receptor expression and regulation. Addition of 17-beta estrogen to mammary tissues markedly increased the expression of progesterone receptor (PR) but only slightly affected that of the estrogen receptor (ER). Medroxyprogesterone acetate down-regulated the expression of PR within 24-48 h and also increased the expression of androgen receptor. When HMG tissue was cultured in medium containing normal or dextran-coated charcoal-stripped fetal calf serum or normal human serum, the expression and regulation of steroid hormone receptors were similar, although different in extent. When serum was omitted, the morphology of HMG was normal after 1 week, but the expression and regulation of ER and PR were altered. Thus, as HMGs retain the capacity to express steroid receptors in culture, this long-term culture system is probably a good model for studying the regulation of the mammary gland by steroids.
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PMID:An in vitro long-term culture model for normal human mammary gland: expression and regulation of steroid receptors. 1259 41

Expression of the 'A' and 'B' forms of progesterone receptor (PR), in an appropriate ratio is critical for normal mammary development. As such, mammary glands of PR-A transgenic mice, carrying additional 'A' form of PR as transgene, exhibit morphological and histological characteristics associated with transformation. Accordingly, in the present studies, we analyzed these mammary glands for the presence of transformed epithelial cells by examining for alterations in gene expressions and growth potential, known to be associated with different stages of transformation. These studies reveal that, in the aberrant mammary epithelial structures, there is a decrease in p21 expression, an increase in cyclin D1 expression accompanied by an increase in cell proliferation, and a decrease in estrogen receptor alpha (ER alpha). In mammary ducts with normal histology, there is a decrease in p21 expression without an elevation in cyclin D1 expression or cell proliferation or a decrease in ER alpha expression. Treatment of PR-A transgenics with anti-progestin, mifepristone, has no effect on cell proliferation, cyclin D1 or ER alpha expression in the aberrant epithelial structures. In contrast, mifepristone restored the loss of p21 expression in the epithelial cells of both the ducts with normal histology and aberrant structures. Parallel studies reveal no apparent differences between the mammary glands of wild-type and PR-B transgenic mice, which carry additional PR 'B' form. Accordingly, we conclude that (i) mammary glands of PR-A transgenics contain at least two distinct populations of transformed epithelial cells, (ii) the epithelial cell population in the ducts with normal histology contain presumptive immortalized cells, indicative of early stages of transformation, (iii) the aberrant epithelial structures contain later stages of transformation associated with hyperplasias/pre-neoplasias and (iv) the transformation of mammary epithelial cells in PR-A transgenics might be due to a misregulation in progesterone action resulting from overexpression of PR 'A' form.
Carcinogenesis 2003 Mar
PMID:Mammary epithelial cells of PR-A transgenic mice exhibit distinct alterations in gene expression and growth potential associated with transformation. 1266 98


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