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

We have examined the ability of 17beta-estradiol (E2) to induce development of mammary cancers in the female ACI rat. Continuous treatment with E2, delivered through release from s.c. Silastic tubing implants containing 27.5 mg crystalline hormone, resulted in rapid development of palpable mammary tumors in ovary-intact ACI rats. In a population of 21 E2-treated rats, palpable tumors were first observed following 99 days treatment and 100% of the treated population developed tumors within 197 days. The median and mean times to appearance of first palpable tumor were 143 and 145 days respectively. All mammary tumors were classified as carcinomas and invasive features were observed. Circulating E2 levels in the treated animals at the time of sacrifice averaged 185 pg/ml serum. Mammary tumors were not observed in ovary-intact female ACI rats that were not treated with E2. This is the first report indicating that this naturally occurring estrogen is capable of inducing mammary cancers in the ACI rat strain. Mammary carcinoma did not develop in a population of 11 ovariectomized female ACI rats treated with E2 for a period of 140 days. Circulating E2 levels in the treated ovariectomized animals averaged 207 pg/ml. These data indicate that the ovary modulates estrogen-mediated mammary carcinogenesis in this rat strain. Both ovary-intact and ovariectomized female ACI rats displayed similar susceptibilities to E2-induced pituitary tumors and hyperprolactinemia. Pituitary weight was increased 6.0-fold in ovary-intact ACI rats and 5.3-fold in ovariectomized female rats. Circulating prolactin levels averaged 2318 ng/ml in E2-treated, ovary-intact rats and 2285 ng/ml in E2-treated, ovariectomized ACI rats. These data indicate that estrogen-induced hyperprolactinemia is not the sole factor leading to development of mammary cancers in the E2-treated ACI rat.
Carcinogenesis 1997 Aug
PMID:Ovary-intact, but not ovariectomized female ACI rats treated with 17beta-estradiol rapidly develop mammary carcinoma. 927 35

Pregnant Wistar-MS rats received whole body irradiation with 2.6 Gy gamma-rays from a 60Co source at day 20 of pregnancy. Control rats were fed a basal diet and were implanted with a diethylstilbestrol (DES) pellet at 30 days after weaning. In the experimental group, rats were fed a diet containing simvastatin immediately after weaning and received a DES pellet at 30 days after weaning. A high incidence of total mammary tumours was observed in the rats fed the control diet and treated with DES for 1 year. The administration of dietary simvastatin together with DES treatment significantly decreased the incidence of mammary tumours. The development of adenocarcinoma in the control rats was significantly higher than that in the rats fed the simvastatin diet. After the administration of simvastatin to the experimental group for 1 year, the serum estradiol-17beta concentration in these rats was markedly reduced, but that of prolactin was not. No significant difference was seen in the development of the mammary glands between rats fed the control diet and those fed the simvastatin diet by whole mount observations. Simvastatin feeding produced an increased development of ER- PgR- tumours and a reduced incidence of ER+ PgR+ tumours. These findings suggest that simvastatin has a potent preventive activity during the DES-dependent promotion/progression phase of radiation-induced mammary tumorigenesis.
Carcinogenesis 1997 Sep
PMID:Anti-carcinogenic activity of simvastatin during the promotion phase of radiation-induced mammary tumorigenesis of rats. 932 67

Peptide hormones and growth factors are involved in the regulation of prostatic cell proliferation, differentiation, and programmed cell death, which functions are primarily controlled by androgen. In carcinogenesis, prostatic cancer cells often lose androgen dependence and become largely dependent on local growth factors. The prostatic cancer cells able to respond to factors other than androgen by proliferation and inhibition of apoptosis are possibly able to survive. We demonstrate that prostatic epithelium expresses prolactin mRNA and protein in a characteristic manner. By using in situ hybridization, an overall distribution of prolactin mRNA was demonstrated in the epithelium of rat dorsal and lateral prostate, whereas a very specific localization of prolactin protein to single cells was observed by immunohistochemistry in the same tissues. In these cells, immunoelectron microscopy showed that prolactin was primarily localized to the secretory granules. These data demonstrate a selective regulation of prostatic prolactin at least at the level of transcript processing/translation and/or protein accumulation and secretion. In addition, the expression of prolactin protein in rat dorsal and lateral prostate was found to be androgen dependent in vivo in castrated and in castrated, testosterone-treated rats, as well as in vitro in organ cultures. Our results support the concept of an autocrine/paracrine loop of prolactin action in prostate where it could mediate some of androgen actions. Also, locally synthesized prolactin might belong to the factors that take over androgen regulation of prostatic cancer cells during the development of androgen-independent growth.
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PMID:Androgen-dependent expression of prolactin in rat prostate epithelium in vivo and in organ culture. 940 49

The cyclin D1/PRAD1 gene is correlated with carcinogenesis of human breast cancer. In this study, we have analyzed effects of breast cancer-related hormones on the cyclin D1 gene expression in T-47D human breast cancer cells. Estradiol (E2) and human prolactin (hPRL) equally enhanced the cyclin D1 gene expression in the cells, and 22 and 20 kDa human growth hormones (22K and 20K hGHs) showed less stimulatory effects. In the presence of E2, however, hPRL or 22K hGH showed additive stimulations of the cyclin D1 gene expression to that by E2 alone, while 20K hGH did not show any additive stimulation of the gene expression. The results suggest that the signal pathways through estrogen and hPRL receptors are important for cyclin D1 gene expression in breast cancer cells, and that 20K hGH has little effect on the cyclin D1 gene expression in these cells because of its lower affinity to PRL receptor.
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PMID:Cooperative and differential effects of estrogen, prolactin, 22K and 20K human growth hormones on cyclin D1/PRAD1 gene expression in T-47D human breast cancer cells. 980 9

Two recent papers demonstrate that prolactin plays an important role in the induction and progression of mammary tumours. Retinoids have been shown to be potent inhibitors of breast carcinogenesis. We studied expression of prolactin receptor mRNA in human breast cancer cell lines MCF-7, SKBR-3, T47D and BT-20 treated with and without retinoids using Northern blot and a quantitative polymerase chain reaction (PCR) method. In all cell lines, all-trans- and 9-cis-retinoic acid, as well as the retinoic acid receptor gamma (RAR-gamma) selective agonists CD2325 and CD437 (1 microM), were able to down-regulate prolactin receptor. After 1 h, a significant reduction was detectable and maximal effect was achieved after 24 h of treatment. Pretreatment with retinoic acid also reduced the prolactin-/prolactin receptor-dependent signal transduction and activation of transcription 5 (STAT-5) activation in T47D cells. Cycloheximide failed to abrogate the retinoic acid-induced decline in prolactin receptor mRNA levels, indicating that this effect was not dependent upon continuing protein synthesis. Similarly, no change in the stability of prolactin receptor mRNA was observed during 12 h of retinoic acid treatment. In conclusion, our results demonstrate that retinoids are able to inhibit the expression of prolactin receptor message, which encodes an important growth factor receptor in breast cancer cells. This action could be responsible for the anti-tumour effects of retinoids.
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PMID:Retinoic acid modulates prolactin receptor expression and prolactin-induced STAT-5 activation in breast cancer cells in vitro. 988 58

Mammary epithelial organoids (MEO), isolated from pubescent rats, were cultured within a reconstituted basement membrane in transwell inserts, in the presence or absence of mature mammary adipocytes in the lower well. This system allowed for free medium exchange between the two compartments, without direct cell-to-cell contact. When cultured in serum-free medium supplemented with insulin, prolactin, hydrocortisone, progesterone, and various epidermal growth factor (EGF) concentrations, mammary adipocytes did not affect epithelial cell growth, but enhanced epithelial differentiation. Casein and lipid accumulations were monitored as indicators of functional differentiation of MEO. Mammary adipocytes significantly enhanced casein and lipid accumulation within the MEO, independently of EGF concentration. Furthermore, adipocytes induced MEO to preferentially undergo alveolar morphogenesis, inhibited squamous outgrowth, and increased lumen size. These findings demonstrate that morphological and functional differentiation of mammary epithelial cells is profoundly enhanced by the adipose stroma and that these effects are mediated by diffusible paracrine factors. This new model can be exploited in future studies to define the mechanisms whereby hormones and growth factors regulate mammary gland development and carcinogenesis. Moreover, it could complement in vivo reconstitution/transplantation studies, which are currently employed to evaluate the role of specific gene deletions in the regulation of mammary development.
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PMID:Adipocyte-epithelial interactions regulate the in vitro development of normal mammary epithelial cells. 1006 68

We have evaluated the chemopreventive effects of curcumin on diethylstilbestrol (DES)-induced tumor promotion of rat mammary glands initiated with radiation. Sixty-four pregnant rats received whole body irradiation with 2.6 Gy gamma-rays from a 60Co source at day 20 of pregnancy and were divided into two groups after weaning. In the control group of 39 rats fed a basal diet and then implanted with a DES pellet for 1 year, 33 (84.6%) developed mammary tumors. Twenty-five rats were fed diet containing 1% curcumin immediately after weaning and received a DES pellet, as for the control. The administration of dietary curcumin significantly reduced the incidence (28.0%) of mammary tumors. Multiplicity and Iball's index of mammary tumors were also decreased by curcumin. Rats fed the curcumin diet showed a reduced incidence of the development of both mammary adenocarcinoma and ER(+)PgR(+) tumors in comparison with the control group. On long-term treatment with curcumin, body weight and ovarian weight were reduced, but liver weight was increased. Compared with the control rats, the curcumin-fed rats showed a significant reduction in serum prolactin, whereas estradiol-17beta and progesterone concentrations were not significantly different between the two groups. Curcumin did not have any effect on the concentration of free cholesterol, cholesterol ester and triglyceride. Feeding of the curcumin diet caused a significant increase in the concentrations of tetrahydrocurcumin, arachidonic acid and eicosapentaenoic acid and a significant decrease in thiobarbituric acid-reactive substance concentration in serum. Whole mounts of the mammary glands showed that curcumin yielded morphologically indistinguishable proliferation and differentiation from the glands of the control rats. These findings suggest that curcumin has a potent preventive activity during the DES-dependent promotion stage of radiation-induced mammary tumorigenesis.
Carcinogenesis 1999 Jun
PMID:Chemoprevention by curcumin during the promotion stage of tumorigenesis of mammary gland in rats irradiated with gamma-rays. 1035 81

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a compound from cooked meat, is an established mammary gland carcinogen in female rats. Four doses of PhIP (150 mg/kg, p.o., once per day) were given to lactating Sprague-Dawley rats separated from their 10-day-old pups to initiate involution of the gland. Twenty-four hours after the last dose, apoptotic index in the mammary gland, as measured by the TUNEL assay, was significantly higher in the gland from control rats than in the PhIP-treated rats (4.757 +/- 1.066 versus 1.905 +/- 0.248%; P < 0.05). In comparison with controls, alveoli in the mammary gland of PhIP-treated rats were also visibly larger and contained more secretory epithelial cells. The expression of Bax, a stimulator of apoptosis, and Bcl-2, an inhibitor of apoptosis, were quantitated by western blotting. Accordingly, Bax expression was 2.7-fold higher in control rats, whereas Bcl-2 expression was 3.1-fold higher in PhIP-treated rats, both changes being statistically different (Student's t-test, P < 0.05). Immunohistochemistry further confirmed a lower expression of Bax and higher expression of Bcl-2 in secretory alveolar epithelial cells of the PhIP-treated mammary gland. The findings are consistent with the notion that exposure to PhIP retarded involution via partial inhibition of programmed cell death. To investigate possible mechanisms for the inhibitory effects of PhIP on mammary gland involution, serum levels of prolactin, an important hormone for the maintenance of lactation, were measured in virgin rats with regular estrous cycles given PhIP (150 mg/kg, p.o.) on the morning of diestrous. After one estrous cycle, on proestrous morning, serum prolactin levels were 1.3-fold higher after PhIP than after control vehicle (one-way ANOVA, Fisher LSD multiple comparison test, P < 0. 05). PhIP exposure during involution was associated with the induction of benign mammary tumors. Seven out of 12 rats developed fibroadenomas, and one developed a tubulopapillary carcinoma within 1 year of receiving PhIP administration during involution (150 mg/kg, p.o., once per day for 5 days), and a high-fat diet (23.5% corn oil). An increase in serum prolactin level and the effects on mammary gland apoptosis seen with PhIP may have implications for the mechanisms of carcinogenic targeting of PhIP to the mammary gland.
Carcinogenesis 1999 Jul
PMID:2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) retards mammary gland involution in lactating Sprague-Dawley rats. 1038 5

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a heterocyclic amine derived from cooked meat. Mammary gland cancer can be induced in female Sprague-Dawley rats by administration of several oral doses of PhIP. The mechanism of mammary gland carcinogenesis by PhIP in this rat model is not fully understood but appears to involve several factors. One factor is the formation of PhIP-DNA adducts in the mammary gland after metabolic activation of PhIP. Possible target cell populations include the epithelial cells of the mammary gland terminal end buds (TEBs), putative sites of origin of carcinomas. Another factor involved in the mammary carcinogenicity of PhIP may be an increased proliferation in epithelial cells of the TEBs which occurs after a carcinogenic dose of PhIP is administered. This proliferation would be likely to enhance the fixation of mutations from PhIP-DNA adducts in target cells and facilitate the initiation of carcinogenesis. PhIP exposure also transiently inhibits the development of the mammary gland by retarding the differentiation of TEBs to alveolar buds and lobules. As a consequence, more TEBs are available for neoplastic transformation. Recent studies in rats have also shown that PhIP increases the levels of serum prolactin, a well-recognized promoter of mammary gland cancer, which may further explain the targeting of PhIP to the mammary gland. The results to date indicate that PhIP has multiple effects on the mammary gland and hormone status in rats that could potentially play a role in its ability to induce mammary gland cancer.
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PMID:Mammary gland carcinogenesis by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in rats: possible mechanisms. 1050 6

Mammary epithelial cell differentiation depends on lactogenic hormones, growth factors, and cell-cell and cell-substrate interactions, all of which modulate transcription factors essential for milk protein gene expression. The CCAAT/enhancer binding protein (C/EBP) family and the signal transducer and activator of transcription 5 (Stat5) have been implicated in mammary epithelial cell growth and differentiation. We have investigated the effects of extracellular matrix components and lactogenic hormones on C/EBP and Stat5 activity. In the mammary gland, tenascin is expressed mainly during embryogenesis and carcinogenesis and in cell culture tenascin downregulates beta-casein gene expression. In HC11 mammary cells, we found that tenascin, but not laminin or fibronectin, specifically downregulated C/EBPalpha levels but had no effect on Stat5 amount or DNA binding activity. Furthermore, we found that the lactogenic hormones, glucocorticoids, prolactin, and insulin, had no effect on C/EBPalpha and C/EBPbeta protein levels but downregulated the DNA binding activity of the transcriptional repressor C/EBPbetaLIP. Thus, C/EBPalpha and beta are regulated by tenascin and lactogenic hormones in mammary epithelial cells.
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PMID:Lactogenic hormones and tenascin-C regulate C/EBPalpha and beta in mammary epithelial cells. 1064 37


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