Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

ECC-1 endometrial cancer cells express estrogen receptor alpha (ER(alpha)), and 17beta-estradiol (E2) induces cell proliferation, cathepsin D mRNA levels, and reporter gene activity in cells transiently transfected with constructs derived from the human cathepsin D and creatine kinase B (pCD and pCKB, respectively) gene promoters. The comparative antiestrogenic activity of aryl hydrocarbon receptor (AhR) agonists and ER(alpha) antagonists were also determined in these endometrial cancer cells. A functional AhR was expressed in ECC-1 cells and AhR agonists including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) inhibited E2-induced cell proliferation and transactivation. This was comparable to inhibitory AhR-ER crosstalk in breast cancer cell lines. The pure ER antagonist ICI 182,780 also exhibited antiestrogenic activity in ECC-1 cells; however, the results obtained for 4'-hydroxytamoxifen were response-specific. 4'-Hydroxytamoxifen alone did not induce ECC-1 cell proliferation but completely inhibited E2-induced cell proliferation. 4'-Hydroxytamoxifen primarily exhibited ER antagonist activities in transactivation assays and this contrasted to the predominant ER agonist responses observed in other endometrial cancer cell lines. The unique cellular context of ECC-1 cells was confirmed using pCKB and constructs expressing wild-type ER or ER variants expressing activation function 1 (AF1) or AF2 (ER-AF1 and ER-AF2, respectively). 4'-Hydroxytamoxifen did not induce reporter gene activity in cells cotransfected with pCKB and ER-AF1 or ER-AF2; however, in cotreatment studies (4'-hydroxytamoxifen plus E2), 4'-hydroxytamoxifen inhibited E2-induced transcriptional activation by ER-AF1 or ER-AF2. Thus, the primarily antiestrogenic activity observed for 4'-hydroxytamoxifen in ECC-1 cells may be related to the inability to activate gene expression through AF1-dependent pathways.
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PMID:Estrogen and aryl hydrocarbon responsiveness of ECC-1 endometrial cancer cells. 1041 Dec 95

Tamoxifen is an anti-oestrogen widely used in the adjuvant therapy of breast cancer and is also used as a prophylactic to prevent the disease in high-risk women. An increased risk of endometrial cancer has been observed in both settings. In rats, tamoxifen potently induces liver carcinomas and also induces uterine tumours when given neonatally. It forms DNA adducts in rat liver via the formation of alpha-hydroxytamoxifen, the ultimately reactive form being generated by sulfotransferase. In order to investigate the formation of tamoxifen-derived DNA adducts in other rat tissues, female Fischer F344 or Sprague-Dawley rats were treated with tamoxifen or alpha-hydroxytamoxifen by gavage or by intraperitoneal injection, daily for 1, 4 or 7 days, and DNA adducts were detected by (32)P-postlabelling analysis. Tamoxifen formed DNA adducts in the liver but not in other tissues (uterus, stomach, kidney, spleen and colon). alpha-Hydroxytamoxifen also formed adducts at high levels in liver, but with the exception of single animals (1/8) in which a low level of adducts was detected in the stomach in one case, and in the kidney in the other; it also did not give rise to adducts in other tissues. The results suggest that tamoxifen is a genotoxic carcinogen in rat liver, but a non-genotoxic carcinogen in rat uterus, making it, uniquely, a carcinogen with more than one mechanism of action. Mutagenicity experiments conducted in Salmonella typhimurium strains expressing bacterial or human N,O-acetyltransferase did not provide evidence that either alpha-hydroxytamoxifen or alpha-hydroxy-N-desmethyltamoxifen undergoes metabolic activation by acetylation. The confinement of ST2A2, the isozyme of hydroxysteroid sulfotransferase that can activate the compounds, mainly to rat liver is the possible reason for the formation of ducts in the liver but not in other organs of the rat.
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PMID:Organ specificity of DNA adduct formation by tamoxifen and alpha-hydroxytamoxifen in the rat: implications for understanding the mechanism(s) of tamoxifen carcinogenicity and for human risk assessment. 1592 12