Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04155 (pS2)
 1,234 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have conducted a clinical trial of a novel pure antiestrogen, 7 alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]estra-1,3,5,(1 0)-triene-3,17 beta-diol (ICI 182780), to assess its tolerance, pharmacokinetics, and short term biological effects in women with primary breast cancer. Fifty-six patients were randomized to either a control group (n = 19), in which they received no preoperative treatment, or a treatment group (n = 37), in which they received daily i.m. injections of ICI 182780 at doses of 6 mg (n = 21) or 18 mg (n = 16) for 7 days prior to primary breast surgery. Serum drug concentrations, gonadotropin levels, and sex hormone-binding globulin levels were measured during the study period by radioimmunoassay. Expression of estrogen receptors (ER), progesterone receptors, the estrogen-induced protein pS2, and the cell proliferation-related antigen Ki67 was determined immunocytochemically in pre- and poststudy tumor samples. Treatment with ICI 182780 caused no serious drug-related adverse events and had no effect on serum gonadotropin or sex hormone-binding globulin levels. Minor adverse events occurred in 5 patients receiving the 6-mg dose and 3 patients receiving the 18-mg dose. The serum concentration of ICI 182780 was dose dependent but showed variation between individuals. There was evidence of an approximately 3-fold drug accumulation over the short treatment period but steady state levels were not reached by the end of the 7 days. In patients with ER-positive tumors, treatment with ICI 182780 was associated with significant reductions in the tumor expression of ER (median ER index, 0.72 before versus 0.02 after treatment; P < 0.001), progesterone receptor (median progesterone receptor index, 0.50 before versus 0.01 after treatment; P < 0.05), and Ki67 (median Ki67 labeling index, 3.2 before versus 1.1 after treatment; P < 0.05). Treatment with ICI 182780 also resulted in a significant reduction in pS2 expression (P < 0.05) but this appeared unrelated to tumor ER status. In conclusion, ICI 182780 was well tolerated after short term administration and produced demonstrable antiestrogenic effects in human breast tumors in vivo, without showing evidence of agonist activity. These properties identify ICI 182780 as a candidate agent with which to evaluate whether a pure estrogen antagonist offers any additional benefit in the treatment of human breast cancer over conventional nonsteroidal antiestrogens, typified by tamoxifen, which exhibit variable degrees of agonist activity.
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PMID:Investigation of a new pure antiestrogen (ICI 182780) in women with primary breast cancer. 827 77

3,3'-Diindolylmethane (DIM), a major in vivo product of acid-catalyzed oligomerization of indole-3-carbinol (I3C), is a promising anticancer agent present in vegetables of the Brassica genus. We investigated the effects of DIM on estrogen-regulated events in human breast cancer cells and found that DIM was a promoter-specific activator of estrogen receptor (ER) function in the absence of 17beta-estradiol (E(2)). DIM weakly inhibited the E(2)-induced proliferation of ER-containing MCF-7 cells and induced proliferation of these cells in the absence of steroid, by approximately 60% of the E(2) response. DIM had little effect on proliferation of ER-deficient MDA-MB-231 cells, suggesting that it is not generally toxic at these concentrations. Although DIM did not bind to the ER in this concentration range, as shown by a competitive ER binding assay, it activated the ER to a DNA-binding species. DIM increased the level of transcripts for the endogenous pS2 gene and activated the estrogen-responsive pERE-vit-CAT and pS2-tk-CAT reporter plasmids in transiently transfected MCF-7 cells. In contrast, DIM failed to activate transcription of the simple E(2)- and diethylstilbesterol-responsive reporter construct pATC2. The estrogen antagonist ICI 182780 (7alpha-[9-[(4,4,5,5, 5-pentafluoropentyl)sulfonyl]nonyl]-estra-1,3,5(10)-triene-3, 17beta-diol) was effective against DIM-induced transcriptional activity of the pERE-vit-CAT reporter, which further supports the hypothesis that DIM is acting through the ER. We demonstrated that ligand-independent activation of the ER in MCF-7 cells could be produced following treatment with the D1 dopamine receptor agonist SKF-82958 [(+/-)6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepinehydrobromide]. We also demonstrated that the agonist effects of SKF-82958 and DIM, but not of E(2), could be blocked by co-treatment with the protein kinase A (PKA) inhibitor H-89 (N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide). These results have uncovered a promoter-specific, ligand-independent activation of ER signaling for DIM that may require activation by PKA, and suggest that this major I3C product may be a selective activator of ER function.
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PMID:Ligand-independent activation of estrogen receptor function by 3, 3'-diindolylmethane in human breast cancer cells. 1082 61