Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pituitary tumor development involves clonal expansion stimulated by hormones and growth factorscytokines. Using mRNA differential display, we found that the bone morphogenetic protein (BMP) inhibitor noggin is down-regulated in prolactinomas from dopamine D2-receptor-deficient mice. BMP-4 is overexpressed in prolactinomas taken from dopamine D2-receptor-deficient female mice, but expression of the highly homologous BMP-2 does not differ in normal pituitary tissue and prolactinomas. BMP-4 is overexpressed in other prolactinoma models, including estradiol-induced rat prolactinomas and human prolactinomas, compared with normal tissue and other pituitary adenoma types (Western blot analysis of 48 tumors). BMP-4 stimulates, and noggin blocks, cell proliferation and the expression of c-Myc in human prolactinomas, whereas BMP-4 has no action in other human pituitary tumors. GH3 cells stably transfected with a dominant negative of Smad4 (Smad4dn; a BMP signal cotransducer) or noggin have reduced tumorigenicity in nude mice. Tumor growth recovered in vivo when the Smad4dn expression was lost, proving that BMP-4Smad4 are involved in tumor development in vivo. BMP-4 and estrogens act through overlapping intracellular signaling mechanisms on GH3 cell proliferation and c-myc expression: they had additive effects at low concentrations but not at saturating doses, and their action was inhibited by blocking either pathway with the reciprocal antagonist (i.e., BMP-4 with ICI 182780 or 17beta-estradiol with Smad4dn). Furthermore, coimmunoprecipitation studies demonstrate that under BMP-4 stimulation Smad4 and Smad1 physically interact with the estrogen receptor. This previously undescribed prolactinoma pathogenesis mechanism may participate in tumorigenicity in other cells where estrogens and the type beta transforming growth factor family have important roles.
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PMID:Involvement of bone morphogenetic protein 4 (BMP-4) in pituitary prolactinoma pathogenesis through a Smad/estrogen receptor crosstalk. 1255 24

Angiogenesis is required during tumor progression. Emerging data, including the presence of estrogen receptors in endothelium, suggests that estrogens can mediate endothelial proliferation and differentiation. Therefore, it is likely that anti-estrogenic drugs can also exert their effects in endothelial cells. The purpose of this work was to evaluate the effect of one anti-estrogenic agent, ICI 182,780, in human umbilical vein endothelial cells (HUVECs). Treatment of HUVECs with 5 different concentrations of ICI 182,780 resulted in decreased cell viability and increase in apoptosis. Gene expression profile of these ICI-treated cells evaluated by cDNA array presented an upregulation of 68 newly expressed genes, whose expression was absent from both control and 17beta-estradiol-treated HUVECs. Most of these genes were implicated in both intrinsic and extrinsic apoptotic pathways. Furthermore, ICI 182,780 incubation prevented HUVECs from formity capillary-like tubules in a Matrigel assay. These findings suggest that besides blocking tumor cell proliferation in an estrogen receptor-dependent manner, ICI 182,780 impaired angiogenesis by preventing branching and capillary-like tubule formation and by activating apoptotic pathways in endothelial cells.
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PMID:Role of the estrogen antagonist ICI 182,780 in vessel assembly and apoptosis of endothelial cells. 1255 34

Estrogens have been shown to regulate vascular endothelial growth factor-A (VEGF-A) for physiological and patho-physiological functions. However, estrogen action on VEGF-A mRNA expression has not been completely elucidated. We have identified two phases of activation of VEGF-A mRNA transcription, one early and one late response, induced by 17beta-estradiol (17beta-E2) in ER+ MCF-7 breast tumor cells, depending upon the length of exposure. VEGF-A mRNA level was significantly higher than control in tumor cells after 2 h of 17beta-E2 exposure. Furthermore this induction was not inhibited by cycloheximide, indicating that it was a direct effect of estrogen. In contrast VEGF-A mRNA expression was back at basal level in MCF-7 cells exposed to 17beta-E2 for 6 h. However, expression levels were again significantly augmented after 24 h of exposure, and this induction was unaltered by cycloheximide indicating that de novo protein synthesis was not required and like early response, it was a direct effect of estrogen. The antiestrogen ICI 182,780 was a pure antagonist for the early response phase of VEGF-A mRNA induction, but it had partial but significant effect on the late response phase, further suggesting that both early and late phases were ER dependent. In human mammary epithelial cells (HMEC) lacking estrogen receptor (ER-alpha) the early and late response phase of VEGF-A mRNA induction in response to 17beta-E2 was not found, but significant inductions were seen in the early and late phases when ER-alpha transfected HMEC were exposed to 17beta-E2 for 2 or 24 h. Taken together, these studies suggest that VEGF-A is an estrogen responsive gene and modulation of this gene expression by estrogen is biphasic and can be mediated through ER-alpha dependent pathway.
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PMID:Estradiol-induced vascular endothelial growth factor-A expression in breast tumor cells is biphasic and regulated by estrogen receptor-alpha dependent pathway. 1257 15

Estrogen action and tuberin function has been suggested to play a crucial role in the proliferation of lung smooth muscle-like cells and/or myofibroblasts in pulmonary lymphangioleiomyomatosis (LAM). Tuberin is a tumor suppressor phosphoprotein, which also regulates fluid phase endocytosis. Its activity, turnover and complex association with hamartin depends on its phosphorylation status. We have recently reported that nongenomic estrogen action regulates the phosphorylation status of several cytoplasmic proteins. Herein, we demonstrate that estrogen increases tyrosine phosphatase activity, which can be abrogated by antiestrogen ICI 182780 and tyrosine phosphatase inhibitor bpV(phen), but not by the protein synthesis inhibitor cyclohexamide. Furthermore, we show that estrogen transiently enhances the turnover of tuberin, which follows an inverse pattern to that observed for tyrosine phosphatase and endocytosis activity. We showed that tuberin phosphorylation protects it from degradation and induces its accumulation in female human lung fibroblasts and myofibroblasts. Our results suggest that nongenomic estrogen action induces tyrosine phosphatase activity that regulates stability of tyrosine phosphorylated proteins, including tuberin, which may play a crucial role in cellular specific functions such as endocytosis.
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PMID:Nongenomic estrogen action regulates tyrosine phosphatase activity and tuberin stability. 1258 86

In three experiments, we evaluated the pharmacological effects of 2-methoxyestradiol (2ME(2)) on several estrogen target tissues. Experiment 1: we gavaged recently ovariectomized (OVX) 9.5-wk-old rats with 2ME(2) at doses of 0, 0.1, 1, 4, 20, and 75 mg/kg in a 21-d dose-response study. 2ME(2) reduced body weight and serum cholesterol, increased uterine weight and epithelial cell height, and inhibited longitudinal and radial bone growth compared with values in the untreated OVX rat. All doses of 2ME(2) maintained cancellous bone mass at the baseline level, the lowest effective dose being 20-fold less than a uterotrophic dose. Experiment 2: in an 8-wk experiment in adult OVX rats, a nonuterotrophic dose of 2ME(2) (4 mg/kg x d) suppressed body weight gain, inhibited bone formation in cancellous bone and partially prevented bone loss in the tibial metaphysis. Experiment 3: in weanling rats, ICI 182,780 did not antagonize the effect of 2ME(2). We conclude that 2ME(2) antagonizes the skeletal changes that follow OVX at doses that have minimal or no effects in the uterus in both young and adult rats; 2ME(2) does not appear to act via estrogen receptors and is active on bone at doses well below those required for tumor suppression in mice. 2ME(2), through a novel pathway, may be a useful alternative to conventional hormone replacement therapy for prevention of postmenopausal bone loss.
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PMID:Dose-response effects of 2-methoxyestradiol on estrogen target tissues in the ovariectomized rat. 1258 54

WISP-2 mRNA and protein was overexpressed in preneoplastic and cancerous cells of human breast. Statistical analyses show a significant association between WISP-2 expression and estrogen receptor (ER) positivity. In normal breast, the expression was virtually undetected. The studies showed that WISP-2 is an estrogen-induced early response gene in MCF-7 cells and the expression was continuously increased to reach a maximum level at 24 h. The estrogen effect was inhibited by a pure antiestrogen (ICI 182,780). Human mammary epithelial cells, in which WISP-2 expression was undetected or minimally detected, responded to 17beta-estradiol by upregulating the WISP-2 gene after transfection with ER-alpha, providing further evidences that WISP-2 expression is mediated through ER-alpha. Overexpression of WISP-2 mRNA by estrogen may be accomplished by both transcriptional activation and stabilization. MCF-7 cells exposed to progesterone had a rapid but transient increase in WISP-2 expression, and PR antagonist RU38486 blocked this mRNA induction. In combination with estradiol, progesterone acted as an antagonist inhibiting the expression of WISP-2 mRNA. Moreover, disruption of WISP-2 signaling in MCF-7 cells by use of antisense oligomers caused a significant reduction in tumor cell proliferation. The results are consistent with the conclusion that WISP-2 expression is a requirement for breast tumor cells proliferation.
Neoplasia
PMID:WISP-2 gene in human breast cancer: estrogen and progesterone inducible expression and regulation of tumor cell proliferation. 1265 71

We examined protein kinase C (PKC) in the regulation of breast cancer cells by estrogen. Estrogen receptor (ER)- positive (+) MCF-7 and ER-negative (-) HCC38 cells were treated with 17 beta-estradiol (E(2)) or E(2)-BSA, which cannot enter the cell. E(2) and E(2)-BSA rapidly increased PKC-alpha in both cells via phosphatidylinositol-dependent phospholipase C and G protein, but not phospholipase A(2) or arachidonic acid. In MCF-7 cells, E(2) and E(2)-BSA had comparable effects, maximal at 90 min. In HCC38 cells, PKC was maximal at 9 min, with E(2)-BSA more than E(2). Tamoxifen blocked estrogen-dependent PKC in MCF-7 cells and reduced it in HCC38 cells. ER-antagonist ICI 182780, ER-agonist diethylstilbestrol, and antibodies to ER alpha and ER beta had no effect. E(2) stimulated [(3)H]thymidine incorporation in MCF-7 only; E(2)-BSA had no effect. Tamoxifen did not alter E(2)-dependent increases in MCF-7 cells, whereas ICI 182780 reduced DNA synthesis in control and E(2)-treated cultures. PKC activity was positively correlated with tumor severity in 133 breast cancer specimens and was greater in ER(-) tumors. Tamoxifen treatment reduced recurrence, and recurrent tumors had higher PKC activity. This indicates that E(2) rapidly increases PKC activity via membrane pathways not involving ER alpha or ER beta and suggests that tamoxifen works by reducing PKC activity through non-ER alpha/ER beta-dependent mechanisms.
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PMID:Estrogen-dependent rapid activation of protein kinase C in estrogen receptor-positive MCF-7 breast cancer cells and estrogen receptor-negative HCC38 cells is membrane-mediated and inhibited by tamoxifen. 1269 87

We employed an in vitro angiogenesis model that simulates the in vivo milieu for tumor capillary formation to study the direct effects of estrogen. 17beta-estradiol (E2) treatment significantly stimulated capillary sprouting within 8 h in co-cultures of rat aortic endothelial cells (RAECs) and mouse mammary tumor cells. Co-cultures treated with either progesterone (P4) or E2+P4 showed minimal endothelial cell (EC) sprouting when compared to E2 treated cultures. Treatment with the E2 agonist ICI 182,780 dramatically inhibited capillary formation, demonstrating E2-specificity. Within hours, of E2 treatment ECs isolated from tumor cell/EC co-cultures demonstrated a statistically significant increase in both mRNA and protein levels of the transcription factor Ets-1. We observed increased matrix metalloproteinase (MMP) and decreased tissue inhibitor of metalloproteinase (TIMP) mRNA levels in these ECs following E2 treatment. Ets-1 upregulates expression of the vascular endothelial growth factor (VEGF) receptor, Flt-1 and we detected increased Flt-1 mRNA levels in ECs co-cultured with tumor cells following E2 treatment. Expression of Ets-1 contributes to destabilization of a quiescent EC phenotype in favor of an invasive angiogenic one, in part, by increasing expression of MMPs and integrin molecules that favor migration and invasion. Transfection of ECs with Ets-1 antisense prior to co-culture with E2 resulted in a 95% inhibition in capillary formation. We demonstrate here, for the first time that nanomolar concentrations of E2 directly and rapidly induced new capillary formation in a mammary tumor/EC co-culture system and suggest that this response may be mediated, in part, by an E2-induced increase in Ets-1 expression.
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PMID:Estrogen-induced Ets-1 promotes capillary formation in an in vitro tumor angiogenesis model. 1272 17

We studied Smad-4dn tumors generated from lactosomatotrophic GH3 cells stably transfected with a dominant negative form of Smad-4 (a bone morphogenetic protein-4, BMP-4, signal co-transducer) which had reduced tumorigenicity in nude mice, but had showed a late increase in tumor size. We found that they had lost in vivo the expression of Smad-4dn and had recovered c-Myc expression. In accordance, BMP-4 is overexpressed and stimulates the expression of c-Myc in human prolactinomas, but not in other human pituitary adenomas or normal pituitary. In addition ICI 182,780 inhibited BMP-4 stimulated c-Myc expression and BMP-4 and 17 beta-estradiol in combination had an additive effect on GH3 cell proliferation. Their action was inhibited by blocking BMP-4 with ICI 182,780 or 17 beta-estradiol with Smad-4dn. Furthermore, co-immunoprecipitation studies demonstrate that Smad-4 physically interacts with the ER alpha/ER beta. We show for the first time the role of BMP-4 in prolactinoma pathogenesis, involving a functional cross-talk BMP-4/E2.
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PMID:[New mechanisms involved in the pathogenesis of pituitary adenomas]. 1279 85

We investigated the influence of estrogenic and antiestrogenic treatment on proteolytic activity--especially on MMP-2 and MMP-13--in the RUCA-I transplantable endometrial tumor model. Morphological studies demonstrate that RUCA-I cells are forming highly differentiated gland-like structures by remodelling and invading the underlying ECM. Estrogens upregulate the mRNA levels of MMP-2 and MMP-13 in the rat uterus. Treatment with the pure antiestrogen ICI 182,780 results in the downregulation of MMP-2 and MMP-13 mRNA. The same regulation for MMP-13 mRNA is found in vitro in RUCA-I cells. In contrast, in the transplantation tumor, the mRNA level of MMP-13 is repressed by estrogens and induced by ICI 182,780. MMP-2 mRNA is not regulated by hormones in the transplantation tumor and in RUCA-I cells. The divergent regulation suggests a varying influence of cell-cell-, cell-extracellular matrix interactions and soluble factors.
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PMID:Estrogenic and antiestrogenic regulation of MMP-2 and MMP-13 mRNA in RUCA-I endometrial tumor cells in vitro and in vivo. 1289 36


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