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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tamoxifen is an effective treatment for breast cancer; however, as well as exerting antagonistic effects on the estrogen receptor (ER), tamoxifen acts as a partial agonists in estrogen-sensitive tissues, resulting in stimulation of the endometrium and tumor growth in some patients who become resistant to treatment.ICI 182, 780 (Faslodex), a steroidal estrogen antagonist, is the first in a new class of agent-an estrogen receptor downregulator. Pre-clinical breast cancer models show that ICI 182, 780 leads to a prolonged duration of response, and that it exerts its effects via a different mode of action to tamoxifen. This was confirmed in a small clinical study involving 19 post-menopausal advanced breast cancer patients, where ICI 182, 780 was highly effective after tamoxifen failure. Definitive evidence of the differing modes of action of ICI 182, 780 and tamoxifen, were provided in a study involving post-menopausal women with primary breast cancer, where analyses of tumor samples following short-term exposure to both drugs, showed that ICI 182, 780 reduced tumor ER levels in a dose-dependent manner, and to a significantly greater extent than tamoxifen. Additionally, unlike tamoxifen, ICI 182, 780 did not promote ER-mediated progesterone receptor expression, indicating that it lacks estrogen agonist activity. Ongoing studies in post-menopausal women with advanced breast cancer are comparing ICI 182, 780 to anastrozole and tamoxifen, respectively. Future studies being considered are whether ICI 182, 780 may also be effective in breast cancer in pre-menopausal women, in early breast cancer and in ductal carcinoma in situ in the breast, in combination with other hormonals, cytotoxics and biological modifiers.
J Steroid Biochem Mol Biol 2001 Dec
PMID:Faslodex (ICI 182, 780), a novel estrogen receptor downregulator--future possibilities in breast cancer. 1185 Feb 27

The objective of this study was to elucidate the biological significance of GnRH and antiprogestins and antiestrogen in leiomyoma and their interactions with ovarian steroid 'add-back' therapy. Leiomyoma and myometrial smooth muscle cells (LSMC and MSMC) were isolated and exposed to GnRH agonist (leuprolide acetate, LA), 17beta-estradiol (E2), medroxyprogesterone acetate (MPA), GnRH antagonist (Antide), estrogen antagonist, ICI182780 (Fulvestrant) and progesterone antagonists RU486 (Mifepristone) and ZK98299 (Onapristone) and combinations thereof. The rate of DNA synthesis, cell proliferation and transforming growth factor-beta (TGF-beta) expression were then determined. In both cell types, we found that in a dose-dependent manner, LA inhibited, whereas E2, MPA and the combination of E2 + MPA stimulated, the rate of DNA synthesis in these cells. Antide reversed the inhibitory effect of LA, while LA partly inhibited the stimulatory effect of the steroids. In addition, RU486, ICI182780 and ZK98299 at 0.1 micro mol/l or higher doses inhibited the rate of DNA synthesis and partly reversed the effects of E2 and/or MPA. We also found that LSMC expressed elevated levels of TGF-beta1 compared with MSMC. In both cell types, the effects of LA, E2, MPA, RU, ZK and ICI and combinations thereof on TGF-beta1 production were reflective of their effects on DNA synthesis. In line with this, TGF-beta1 was found to stimulate DNA synthesis and the E2-, TGF-beta1- or E2 + TGF-beta1-induced DNA synthesis was found to be inhibited by TGF-beta1 neutralizing antibodies and/or LA. In conclusion, the results provide further evidence that GnRH agonist- and RU486-induced leiomyoma regression is mediated in part through an interactive mechanism that results in altered cell growth and suppression of TGF-beta production.
Mol Hum Reprod 2002 Dec
PMID:Effects of GnRH analogues, 'add-back' steroid therapy, antiestrogen and antiprogestins on leiomyoma and myometrial smooth muscle cell growth and transforming growth factor-beta expression. 1246 39

In order to understand the mechanisms underlying the development of resistance to a pure antiestrogen we established three human breast carcinoma cell lines resistant to ZM 182780 (ZM) (Faslodex). Long-term cultivation of the ERalpha-positive, 17beta-estradiol (E(2))-responsive cell lines T47D, ZR-75-1, and MCF-7 with the pure antiestrogen ZM 182780 resulted in the T47D-r, ZR-75-1-r, and MCF-7-r cell lines, which proliferate continuously in the presence of 10(-6)M ZM 182780. The resulting antiestrogen-resistant cells grow equally well in medium with or without E(2) and in medium with or without ZM 182780 indicating that they are no longer estrogen-responsive. ERalpha expression was lost at the protein level in all three resistant cell lines. At the mRNA level, the ERalpha was only faintly detectable in T47D-r, whereas a weak signal was seen in ZR-75-1-r and MCF-7-r. By reverse transcription-polymerase chain reaction (RT-PCR) the ERbeta was detectable in the antiestrogen-sensitive and -resistant breast cancer cell lines, however, ZR75-1-r contained the smallest signal for ERbeta. In all three antiestrogen-resistant cells the PR was undetectable, whereas binding of epidermal growth factor (EGF) and protein expression of epidermal growth factor receptor (EGFR) were increased. To analyse alterations in the gene expression pattern in more detail Atlas arrays were hybridised with RNA isolated from T47D-r and T47D and the two Ca2+-binding proteins calgranulin A and B were found to be up-regulated in T47D-r compared to T47D. Calgranulin A and B were also both up-regulated in ZR-75-1-r and MCF-7-r compared to their antiestrogen-sensitive counterparts. Loss of ERalpha expression may be linked to the acquisition of antiestrogen resistance and enhanced expression of the EGFR and of proteins of the S100 family of Ca2+-binding proteins which may contribute to the outgrowth of resistant cells.
J Steroid Biochem Mol Biol 2003 May
PMID:Studies on the development of resistance to the pure antiestrogen Faslodex in three human breast cancer cell lines. 1279 55

In search of novel mechanisms leading to the development of antiestrogen-resistance in human breast tumors, we analyzed differences in the gene and protein expression pattern of the human breast carcinoma cell line T47D and its derivative T47D-r, which is resistant toward the pure antiestrogen ZM 182780 (Faslodex trade mark, fulvestrant). Affymetrix DNA chip hybridizations on the commercially available HuGeneFL and Hu95A arrays were carried out in parallel to the proteomics analysis where the total cellular protein content of T47D or T47D-r was separated on two-dimensional gels. Thirty-eight proteins were found to be reproducibly up- or down-regulated more than 2-fold in T47D-r versus T47D in the proteomics analysis. Comparison with differential mRNA analysis revealed that 19 of these were up- or down-regulated in parallel with the corresponding mRNA molecules, among which are the protease cathepsin D, the GTPases Rab11a and MxA, and the secreted protein hAG-2. For 11 proteins, the corresponding mRNA was not found to be differentially expressed, and for eight proteins an inverse regulation was found at the mRNA level. In summary, mRNA expression data, when combined with proteomic information, provide a more detailed picture of how breast cancer cells are altered in their antiestrogen-resistant compared with the antiestrogen-sensitive state.
Mol Cell Proteomics 2004 Jan
PMID:Comparison of proteomic and genomic analyses of the human breast cancer cell line T47D and the antiestrogen-resistant derivative T47D-r. 1455 97

Faslodex (FAS, ICI 182, 780), a novel steroidal estrogen antagonist decreased high-dose methotrexate (MTX) cytotoxicity in MCF-7 breast cancer cells. When FAS is given at least 24 hr prior to MTX, the resultant interaction is antagonistic. However, when breast cancer cells are exposed to FAS 24 hr after MTX, the interaction between FAS and MTX is not antagonistic. The proliferation of cells exposed to 0.1 microM FAS and 10 microM MTX alone or in combination with FAS 24 hr prior to MTX was in the following order: FAS>FAS 24 hr prior to MTX>MTX. MTX administration 24 hr prior to FAS had the following inhibitory effects on the growth of cells: MTX 24 hr prior to FAS >MTX>FAS 24 hr prior to MTX>FAS>control (no drug exposure). To determine if the antagonistic interaction between FAS and MTX was a function of sequence and time, cells were exposed to FAS 24 hr and 36 hr prior to MTX exposure. The percentages of control rates were 42.70 +/- 4.60% and 57.89 +/- 0.55%, respectively, from a 24 hr and 36 hr exposure of FAS prior to MTX. The growth rates after 24 and 36 hr exposures to MTX alone were 30.30 +/- 0.61% and 33.11 +/- 2.57% of control rates, respectively. These studies suggest that: a) the interactions between FAS and MTX are sequence-dependent; b) FAS antagonizes the effect of MTX when FAS administration precedes MTX, and c) FAS antagonism to MTX is a function of time.
Cell Mol Biol (Noisy-le-grand) 2003 Nov
PMID:The interaction of the steroidal antagonist faslodex and methotrexate. 1468 88

Investigating three somatostatin receptor (SSTR)-positive (+) human breast cancer cell lines, Xu et al. found a time- and dose-dependent up- or down-regulation of SSTR2 mRNA expression by 17beta-oestradiol (E(2)) or the anti-oestrogen tamoxifen, respectively, in the two oestrogen receptor-positive (ER+) cell lines but not in the oestrogen receptor-negative (ER-) cell line. This study aimed to confirm the findings of Xu et al. at the protein level by means of western blotting and saturation binding studies using (99m)Tc-depreotide (NeoSpect). The ER+/SSTR+ ZR75-1 and T47D and SSTR+/ER- MDA MB231 breast cancer cell lines were exposed to 1 n M E(2) or a combination of 1 n M E(2) plus 100 n M tamoxifen or ICI 182 780 (Faslodex) for 48 h. Exposed and non-exposed controls were incubated with increasing concentrations of (99m)Tc-depreotide (0.5 n M-15 n M) in the absence and the presence of 20 micro M of octreotide. Scatchard-Rosenthal plots were derived using commercially available software. SSTR subtypes responsible for E(2)-induced changes in (99m)Tc-depreotide binding were identified by means of western blotting. Mean K(d) values for (99m)Tc-depreotide were 13 n M, 7 n M and 4 n M for T47D, ZR75-1 and MDA MB231 cells, respectively. After stimulation with E(2), the ER+ cell line T47D demonstrated a mean increase of 81% ( P<0.05) in (99m)Tc-depreotide binding. Adding the partial agonist tamoxifen and full antagonist ICI 182 780 to E(2) blocked the induced increase in T47D cells, either reducing SSTR expression or restoring it to control levels. ZR75-1 cells stimulated with E(2) showed a mean decrease in (99m)Tc-depreotide binding of 36% as compared to control cells; this difference, however, proved to be not statistically significant. Similarly, B(max) values did not change in ZR75-1 cells exposed to E(2) in combination with an ER antagonist as compared to control cells. Finally, no influence of E(2) on (99m)Tc-depreotide binding was observed in the ER- cell line MDA MB231. Both SSTR2 and SSTR5 were expressed at high levels in T47D cells and ZR75-1 cells. SSTR5 drastically increased in the absence of E(2) and was restored to the original detection level after E(2) treatment. The presented findings support an oestrogen-dependent regulation of SSTR expression in breast cancer cell lines.
Eur J Nucl Med Mol Imaging 2004 Jul
PMID:Oestrogen-mediated regulation of somatostatin receptor expression in human breast cancer cell lines assessed with 99mTc-depreotide. 1502 61

The effects of estrogen receptor (ER) ligands on the stability and transcriptional activity of ERbeta in the breast cancer cell lines MCF-7 and HeLa were examined. We found that ERbeta was degraded in the presence of 17beta-estradiol. Tamoxifen and Faslodex (ICI 182,780) prevented ERbeta receptor destabilization. In contrast to ERalpha, ERbeta degradation was not abolished by inhibitors of the proteasome-mediated protein degradation pathway. Furthermore, single point mutations in helix 12 of the receptor dramatically affected the stability and subsequent transcriptional activation of ERbeta.
J Mol Endocrinol 2004 Jun
PMID:Distinct effects of the antiestrogen Faslodex on the stability of estrogen receptors-alpha and -beta in the breast cancer cell line MCF-7. 1517 27

Estrogen receptor regulation of nitric oxide production by vascular endothelium may involve rapid, membrane-initiated signaling pathways in addition to classic genomic mechanisms. In this study, we demonstrate using intact cerebral blood vessels that 17beta-estradiol rapidly activates endothelial nitric-oxide synthase (eNOS) via a phosphoinositide-3 (PI-3) kinase-dependent pathway. The effect is mediated by estrogen receptors (ERs), consistent with colocalization of ERalpha and caveolin-1 immunoreactivity at the plasma membrane of endothelial cells lining cerebral arteries. Treatment with 10 nM 17beta-estradiol for 30 min increased NO production, as measured by total nitrite assay, in cerebral vessels isolated from ovariectomized rats. This effect was significantly decreased by membrane cholesterol depletion with beta-methyl-cyclodextrin, the ER antagonist ICI 182,780 [fulvestrant (Faslodex)], and two inhibitors of PI-3 kinase: wortmannin and LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride]. In parallel with NO production, 17beta-estradiol treatment rapidly increased phosphorylation of both eNOS (p-eNOS) and Akt (p-Akt). PI-3 kinase inhibitors also blocked the latter effects; together, these data are consistent with ER activation of the PI-3 kinase-p-Akt-p-eNOS pathway. ERalpha protein (66 and 50 kDa) coimmunoprecipitated with eNOS as well as with the p85alpha regulatory subunit of PI-3 kinase, further implicating ERalpha in kinase activation of eNOS. Little is known regarding the effects of estrogen on cellular kinase pathways in vivo; therefore, we compared cerebral blood vessels isolated from ovariectomized rats that were either untreated or given estrogen replacement for 4 weeks. Long-term estrogen exposure increased levels of cerebrovascular p-Akt and p-eNOS as well as basal NO production. Thus, in addition to the rapid activation of PI-3 kinase, p-Akt, and p-eNOS, estrogen signaling via nontranscriptional, kinase mechanisms has long-term consequences for vascular function.
Mol Pharmacol 2005 Jan
PMID:Estrogen receptor activation of phosphoinositide-3 kinase, akt, and nitric oxide signaling in cerebral blood vessels: rapid and long-term effects. 1549 4

The molecular mechanisms underlying the acquisition of resistance to the antiestrogen Faslodex are poorly understood, although enhanced expression and activity of nuclear factor kappaB (NFkappaB) have been implicated as a critical element of this phenotype. The purpose of this study was to elucidate the mechanism by which NFkappaB up-regulation contributes to Faslodex resistance and to determine whether pharmacologic inhibition of NFkappaB by the small molecule parthenolide could restore Faslodex-mediated suppression of cell growth. Basal expression of multiple NFkappaB-related molecules in MCF7-derived LCC1 (antiestrogen-sensitive) and LCC9 (antiestrogen-resistant) breast cancer cells was determined, and cells were treated with Faslodex or parthenolide. The effect of these drugs either singly or in combination was assessed by cell proliferation, estrogen receptor (ER)-dependent transcriptional activation, cell cycle analysis, and apoptosis assays. Expression of the p65 NFkappaB subunit and the upstream NFkappaB regulator IkappaB kinase gamma/NFkappaB essential modulator were increased in the resistant MCF7/LCC9 cells (P=0.001 and 0.04, respectively). Whereas MCF7/LCC9 cells were unresponsive to Faslodex alone, parthenolide effectively inhibited MCF7/LCC9 cell proliferation and the combination of Faslodex and parthenolide resulted in a 4-fold synergistic reduction in cell growth (P=0.03). This corresponded to a restoration of Faslodex-induced apoptosis (P=0.001), with no observable changes in ER-dependent transcription or cell cycle phase distribution. Because parthenolide has shown safety in Phase I clinical trials, these findings have direct clinical relevance and provide support for the design of clinical studies combining antiestrogens and parthenolide in ER-positive breast cancer.
Mol Cancer Ther 2005 Jan
PMID:The nuclear factor kappa B inhibitor parthenolide restores ICI 182,780 (Faslodex; fulvestrant)-induced apoptosis in antiestrogen-resistant breast cancer cells. 1565 51

We report here that estrogen (E(2)) modulates mitochondrial function in the vasculature. Mitochondrial dysfunction is implicated in the etiology of vascular disease; thus, vasoprotection by estrogen may involve hormonal effects on the mitochondria. To test this hypothesis, mitochondria were isolated from cerebral blood vessels obtained from ovariectomized female rats, with or without E(2) replacement. Estrogen receptor-alpha (ER-alpha) was detected in mitochondria by immunoblot and confocal imaging of intact vessels. E(2) treatment in vivo increased the levels of specific proteins in cerebrovascular mitochondria, such as ER-alpha, cytochrome c, subunit IV of complex IV, and manganese superoxide dismutase, all encoded in the nuclear genome, and subunit I of complex IV, encoded in the mitochondrial genome. Levels of glutathione peroxidase-1 and catalase, however, were not affected. Functional assays of mitochondrial citrate synthase and complex IV, key rate-limiting steps in energy production, showed that E(2) treatment increased enzyme activity. In contrast, mitochondrial production of hydrogen peroxide was decreased in vessels from E(2)-treated animals. In vitro incubation of cerebral vessels with 10 nM 17beta-estradiol for 18 h also elevated levels of mitochondrial cytochrome c. This effect was blocked by the estrogen receptor antagonist fulvestrant (ICI-182,780, Faslodex) but was unaffected by inhibitors of nitric-oxide synthase or phosphoinositide-3-kinase. Nuclear respiratory factor-1 protein, a primary regulator of nuclear gene-encoded mitochondrial genes, was significantly increased by long-term estrogen treatment in vivo. In summary, these novel findings suggest that vascular protection by E(2) is mediated, in part, by modulation of mitochondrial function, resulting in greater energy-producing capacity and decreased reactive oxygen species production.
Mol Pharmacol 2005 Oct
PMID:Estrogen increases mitochondrial efficiency and reduces oxidative stress in cerebral blood vessels. 1599 67


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