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PubMed1998

Tamoxifen inhibits induction of the mitochondrial permeability transition by Ca2+ and inorganic phosphate.

Tamoxifen (TAM) is a synthetic, nonsteroidal antiestrogenic agent that is widely prescribed in the treatment of estrogen-dependent neoplasias, including breast cancer. The mechanism of action has yet to be defined, but likely is independent of estrogen receptor binding. In light of its high lipophilicity and peroxyl radical scavenging activities, we hypothesized that TAM might be an effective inhibitor of the mitochondrial permeability transition (MPT), which is widely implicated in the mechanisms of chemical-induced tissue injury and apoptosis. The MPT was induced in vitro by incubating freshly isolated rat liver mitochondria in 1 mM Pi with increasing concentrations of calcium. Induction of the MPT was characterized by the calcium-dependent depolarization of mitochondrial membrane potential, release of matrix calcium, and large amplitude swelling. Membrane potential and calcium release were measured with ion-selective electrodes; mitochondrial swelling was monitored spectrophotometrically. Preincubation with either cyclosporine A or TAM prevented, in a dose-dependent manner, the calcium-induced MPT. TAM also inhibited the calcium-induced release of matrix glutathione. TAM caused a time-dependent reversal of both the calcium-induced membrane depolarization and calcium release, suggesting that the effect was on the permeability transition pore and not due to inhibition of the mitochondrial calcium uniport. The results suggest that TAM mimics cyclosporine A to inhibit induction of the MPT and that this activity is not related to the antioxidant properties of TAM.

Animals↗
PubMed1993

Toremifene and tamoxifen in advanced breast cancer--a double-blind cross-over trial.

Toremifene (TOR) is a triphenylethylene derivative related to tamoxifen (TAM). TOR has antitumor activity, not dependent on estrogen receptors, and responses with TOR have been observed in patients with progressive disease during TAM-treatment. To elucidate possible cross-resistance between these two antiestrogens, we compared their anti-tumor activity in a randomized, double-blind, cross-over study. 66 postmenopausal women with advanced estrogen receptor positive or unknown breast cancer and a median age of 63 years (range 38-82) were included. Patients were randomized to TAM 40 mg/day or TOR 240 mg/day. Treatment continued until progressive disease, when cross-over to the alternative treatment was done. The response rate with first line TOR was 29% (95% confidence limits 10-41%) and with TAM 42% (95% confidence limits 25-61%). Response rates and response durations, survival and toxicity were not significantly different between the two treatments. 44 patients progressing on first line TAM or TOR were evaluable for second line TOR or TAM treatment. As no responses were observed, the possibility of over-looking a response rate of 20% or more is less than 1%. In conclusion, this study strongly indicates that TOR and TAM are clinically cross-resistant in patients with advanced breast cancer.

Adult↗
PubMed1994

The estrogen receptor from a tamoxifen stimulated MCF-7 tumor variant contains a point mutation in the ligand binding domain.

The nonsteroidal antiestrogen tamoxifen (TAM) is the most commonly used endocrine treatment for all stages of breast cancer in both pre- and postmenopausal women. However, the development of resistance to the drug is common, as most patients treated with TAM eventually experience a recurrence of tumor growth. One of the potential mechanisms of treatment failure is the acquisition by the tumor of the ability to respond to TAM as a stimulatory rather than inhibitory ligand. We (Gottardis and Jordan, Cancer Res 48:5183-5187, 1988; Wolf et al., J Natl Cancer Inst 85:806-812, 1993) and others (Osborne et al., Eur J Cancer Clin Oncol 23: 1189-1196, 1987; Osborne et al., J Natl Cancer Inst 83: 1477-1482, 1991) have extensively described the reproducible development of TAM stimulated growth in a laboratory model system using MCF-7 human breast cancer cells grown as solid tumors in athymic mice. In this paper we report on the isolation of an estrogen receptor (ER) from a TAM stimulated tumor (MCF-7/MT2) which contains a point mutation that causes a tyrosine for aspartate substitution at amino acid 351 in the ligand binding domain. The mutant appears to the major form of ER expressed by this tumor. We also report that only wild type ER was detected in three other TAM stimulated MCF-7 tumor variants, suggesting that multiple mechanisms are possible for the development of TAM stimulated growth. The implications of these findings are discussed.

Amino Acid Sequence↗
PubMed1996

A randomized trial comparing ftorafur alone with ftorafur plus tamoxifen in postoperative adjuvant therapy for breast cancer. Kinki Area Research Group for Postoperative Adjuvant Therapy for Breast Cancer.

A randomized study was performed in 35 centers in the Kinki area of Japan to determine the effectiveness of ftrorafur (FT) plus tamoxifen (TAM) compared with FT monotherapy in postoperative adjuvant therapy for breast cancer. Patients were randomized by the envelope method to receive either FT 600 mg/day or FT 600 mg/day plus TAM 20 mg/day orally for 1 year, starting on day 7 after mastectomy. Between April 1982 and January 1985, 628 patients were assigned to treatment with FT alone and 626 to treatment with FT + TAM. Of these, 571 (90.9%) and 539 (86.1%) patients, respectively, met the eligibility requirements for this study. There were no significant differences in major background factors between the two groups of eligible patients. Five-year survival rates were 91.4% for FT alone and 91.1% for FT+TAM (not significantly different). Five-year disease-free survival rates showed a tendency towards a better prognosis (P = 0.090) in the FT + TAM group, with observed rates of 83.0% for FT alone and 86.7% for FT + TAM. Stratified analysis showed that disease-free survival with FT + TAM is better than with FT alone for patients aged 50 years or more ( P = 0.048) and for patients with from one to three positive nodes (P = 0.064).

Adult↗
PubMed1997

Monocyte chemoattractant protein-1 expression and macrophage infiltration in gliomas.

While the number of reports on macrophage infiltration of gliomas is increasing, the extent and mechanisms of macrophage recruitment remain unclear. To investigate whether monocyte chemoattractant protein-1 (MCP-1) plays a role in this process, in situ hybridisation (ISH) was performed for 22 glioblastomas (GBM), 1 anaplastic astrocytoma (AA) and 4 grade II fibrillary astrocytomas (AII) and reverse transcription-polymerase chain reaction was performed in 13 GBM, 1 AA and 3 AII. High levels of MCP-1 mRNA were detectable in most GBM, while a lower level was detected in AII. Many tumour-associated macrophages (TAM) could be demonstrated by immunohistochemistry (IHC) in most GBM, while the AII contained a lower number of TAM. The positive correlation between the MCP-1 level and abundance of TAM suggested that MCP-1 has a role in TAM recruitment. By combining ISH and IHC, high levels of MCP-1 mRNA were shown both in tumour cells and TAM. Along tumour borders, reactive astrocytes and microglia also expressed MCP-1. In areas with T lymphocyte infiltration, larger numbers of MCP-1-positive cells with an enhanced level of expression could be identified. We propose that the mechanism of macrophage recruitment is, at least partly, effected by constitutive expression and T cell-mediated up-regulation of MCP-1 in tumour cells and TAM. The production of MCP-1 by TAM establishes a positive amplification circuit for macrophage recruitment in gliomas.

Astrocytoma↗
PubMed2004

Crossover trial for lipid abnormality in postmenopausal breast cancer patients during selective estrogen receptor modulators (SERMs) administrations.

The objective of this study was to evaluate the different profiles of serum lipids resulting from the administration of selective estrogen receptor modulators (SERMs). Postmenopausal primary breast cancer patients (n = 197) with node-negative, hormone receptor-positive who were treated at our department or in other related medical institutions from April 1997 through March 2001 were given adjuvant therapy. The adjuvant therapy included 1 year's administration of tamoxifen (TAM) 20 mg or toremifene (TOR) 40 mg. The profiles of serum lipids such as total cholesterol (TC), high-density lipoprotein cholesterol (HDL) and triglyceride (TG) were observed. After 1 year administration TC had significantly decreased (p < 0.001) both in the TAM group and the TOR group, but no significant difference was found between these groups (p = 0.249). HDL had significantly decreased in the TAM group (p < 0.001), while it had significantly increased in the TOR group (p < 0.001), and a significant difference was found between the groups (p < 0.001). TG had significantly increased in the TAM group (p < 0.001) but significantly decreased in the TOR group (p < 0.001). The medication was switched in those who still had abnormal lipid metabolism and given to them for another year. After 1 year from the crossover TC and HDL had increased to the levels of before administration (p < 0.001) and TG had decreased in those (n = 57) whose medication was switched from TAM to TOR. While TC had decreased and TG had increased in those (n = 23) whose medication was switched from TOR to TAM (p < 0.001). The above findings have suggested that TOR provides better profiles of lipid metabolism than TAM.

Administration, Oral↗
PubMed2005

Bidirectional cross talk between ERalpha and EGFR signalling pathways regulates tamoxifen-resistant growth.

We have previously demonstrated that oestrogen receptor alpha (ERalpha) modulates epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK) signalling efficiency in a tamoxifen-resistant MCF-7 breast cancer cell line (Tam-R). In the present study we have investigated whether this cross-talk between EGFR/MAPK and ERalpha signalling pathways is bidirectional by examining the effects of EGFR/MAPK activity on ER functionality in the same cell line. Elevated expression levels of phosphorylated serine 118 (S118) ERalpha were observed in the Tam-R compared to the parental wild type MCF-7 cell line (WT-MCF-7) under basal growth conditions. Phosphorylation of ERalpha at S118 was regulated by the EGFR/MAPK pathway in Tam-R cells being increased in response to amphiregulin (AR) and inhibited by the selective EGFR tyrosine kinase inhibitor, gefitinib and the MEK1/2 inhibitor, PD184352. Recruitment of the co-activators p68 RNA helicase and SRC1 to ERalpha, oestrogen response element (ERE) activity and Tam-R cell growth were similarly EGFR/MAPK-regulated. Chromatin immunoprecipitation (ChIP) studies revealed that in Tam-R cells the ERalpha assembled on the AR gene promoter and this was associated with elevated basal expression of AR mRNA. Furthermore, AR mRNA expression was under the regulation of the EGFR/MAPK and ERalpha signalling pathways. Neutralising antibodies to AR inhibited EGFR/ERK1/2 activity, reduced S118 ERalpha phosphorylation and reduced AR mRNA expression in TAM-R cells. These findings suggest that ERalpha function in Tam-R cells is maintained as a consequence of EGFR/MAPK-mediated phosphorylation at serine residue 118 resulting in the generation of a self-propogating autocrine growth-regulatory loop through the ERalpha-mediated production of AR.

Antineoplastic Agents, Hormonal↗
PubMed1992

Embryonic differentiation of sexual dimorphism in vasotocin and mesotocin levels in chickens.

Chicken embryos of both sexes were injected on the tenth day of incubation with either estradiol benzoate (EB), aromatase inhibitor [1,4,6-androstatrien-3, 17-dione (ATD)], antiestrogen [tamoxifen (TAM)], antiandrogen [flutamide (FLU)], or the oil vehicle as control (C). At adulthood, at the age of 26 weeks, 10 chickens of each sex were killed and the amounts of immunoreactive arginine vasotocin (AVT) and mesotocin (MT) in the anterior hypothalamus (AHA), posterior hypothalamus (PHA), neurohypophysis (NHP), and pineal gland (PNL) were determined. Control hens had significantly more AVT in PNL and less MT in AHA and NHP than the corresponding roosters. This sexual dimorphism was affected by the embryonic treatments; TAM increased AVT in AHA of cockerels but not of hens. In both sexes, TAM and FLU increased AVT content in NYP. In males, but not in females, ATD also increased AVT content in the NHP. TAM and FLU administration to the female embryo reduced PNL AVT to the amount present in normal males. None of the treatments effected AHA MT in hens, while in cockerels TAM increased it. In females, TAM and FLU significantly increased NHP MT to the level of C males. In roosters, ATD, TAM, and FLU increased NHP MT further. In hens, but not roosters, FLU reduced MT in PNL. These results indicate that embryonic differentiation of the MT and AVT systems is affected by gonadal steroids in chickens.

Animals↗
PubMed1985

The Christie Hospital tamoxifen (Nolvadex) adjuvant trial for operable breast carcinoma--7-yr results.

The Christie Hospital Tamoxifen Trial was a randomised trial to assess the efficacy of tamoxifen (Nolvadex) as an adjunct to surgical treatment for operable breast carcinoma. From 1 November 1976 to 1 June 1982 1005 patients were registered, of whom 961 are evaluable. Following surgery, premenopausal women were randomly allocated to either tamoxifen (TAM) 20 mg/day for 1 yr or to have an irradiation menopause. Postmenopausal women had TAM 20 mg/day for 1 yr or no further treatment (controls). The analysis at 7 yr shows that there is no statistically significant difference in the overall survival for premenopausal women between those given TAM and those given ovarian irradiation. Similarly for the postmenopausal women there was no significant difference in overall survival between the TAM and control groups. However, if the series of 961 patients is analysed as a whole and allowance is made for node status then the TAM-treated patients show a significant survival benefit (P = 0.05). There was also a statistically significant delay in first relapse for the TAM-treated patients (P = 0.04); with a particularly marked reduction in distant metastases in postmenopausal patients (P = 0.06). TAM was extremely well tolerated, with very few side-effects.

Adult↗
PubMed1988

Effect of tamoxifen and tamoxifen derivatives on the conversion of estrone sulfate to estradiol in the MCF-7 mammary cancer cell line.

The human mammary cancer cell line MCF-7 in culture was used to study the effect of tamoxifen and its derivatives: 4-hydroxytamoxifen (4-OH-Tam), N-desmethyltamoxifen (Dem-Tam) and cis-tamoxifen (cis-Tam) on the uptake and conversion of [3H]estrone sulfate (3H-E1S) to estradiol (E2). When [3H]-E1S (4 X 10(-9) M) was incubated by itself (control) a great proportion of the radioactivity was found as [3H]E2, predominantly in the nuclear fraction. All of the anti-estrogens (10(-6) M - 10(-5) M) studied decreased the total uptake of radioactivity by the cells by 50-60% and the quantity of E2 formed. The calculated concentrations (in pg/mg DNA +/- S.E.M.) of E2 (cytosol + 0.6 M KCl nuclear extract) with the anti-estrogens at 10(-5) M were as follows: control 56 +/- 3; Tam treated cells 4 +/- 1; + 4-OH-Tam 2 +/- 1; + Dem-Tam 5 +/- 2; + cis-Tam 8 +/- 4. A significant decrease in the concentrations of E2 was also observed in the mitochondria-microsomal fractions after the different treatments. It is suggested that the MCF-7 cells can use estrone-3-sulfate as a source of E2 and that the inhibitory effect of tamoxifen and its derivatives on the conversion of this sulfate to E2 could be involved in the anti-estrogenic process of these triphenylethylene derivatives.

Breast Neoplasms↗
PubMed1992

Interaction of DP-TAT-59, an active metabolite of new triphenylethylene-derivative (TAT-59), with estrogen receptors.

DP-TAT-59, (Z)-2-(4-(1-(4-hydroxyphenyl)-2-(4-isopropylphenyl)-1-butenyl) phenoxy)-N, N-dimethylethylamine, has been reported to inhibit estrogen-stimulated growth of MCF-7 cells as well as rat uterus at lower concentrations than the hydroxymetabolite of tamoxifen (4-OH-TAM). In the present study, the growth of mouse Leydig cell tumor, B-1F cells were also more effectively inhibited by DP-TAT-59 than 4-OH-TAM. Additionally, the expression of estrogen responsive element ligated CAT gene transfected into B-1F cells was also suppressed by DP-TAT-59. Thus, the interaction of DP-TAT-59 with estrogen receptor (ER) was characterized and compared with that of 4-OH-TAM using immature rat and bovine uteri. The dissociation constant of DP-TAT-59 to ER of immature rat uterus was 0.24 nM and was similar to that of 4-OH-TAM (Kd = 0.20 nM) and estradiol (Kd = 0.29 nM). Using sucrose density gradients, the sedimentation constant of DP-TAT-59 with bovine uterus was 4.9S, which was similar to that of estradiol (5.1S) and 4-OH-TAM (5.3S). However, the elution profile of the DP-TAT-59-ER complex from a DEAE-Sephadex column was different for both estradiol-and 4-OH-TAM-ER complexes. These results suggest that ER forms different complexes with DP-TAT-59 than estradiol or 4-OH-TAM, while the ER binding affinity of these compounds are similar to each other.

Animals↗
PubMed2006

Biotransformation of letrozole in rat liver microsomes: effects of gender and tamoxifen.

The in vitro metabolic kinetics of letrozole were investigated by incubating letrozole (10-500 microM) in female or male rat liver microsomes to assess the effect of gender and to predict the in vivo biotransformation characteristics of letrozole in rats. The effects of tamoxifen (TAM) on the metabolic kinetics of letrozole were also examined by incubating letrozole in female rat liver microsomes in the presence or absence of TAM. The effects of chronic pretreatment of female rats with TAM (0.5, 1.0, 5.0 mg/kg/day, i.p. for 7 consecutive days) on liver microsomal protein content and metabolic activity were also examined. The formation rate of the carbinol metabolite of letrozole, CGP44 645, was significantly higher (p<0.05) in male rat liver microsomes in comparison to female. The V(max)/K(m) ratio for letrozole metabolism in female rat liver microsomes did not change significantly (p>0.05) in the presence of TAM. After chronic pretreatment of female rats with TAM (up to a dose of 1.0mg/kg/day), the hepatic microsomal protein content was significantly increased but the formation rate of CGP44 645, when normalized for protein content, did not change significantly. These results suggest that there is a marked gender difference in letrozole metabolism in rats. It also appears that acute treatment of female rat liver microsomes with TAM produces negligible inhibitory effect on the CYP mediated metabolic clearance of letrozole. However, chronic pretreatment of female rats with TAM appear to induce CYPs, but does not significantly impact the metabolic activities of the enzymes associated with the formation of the carbinol metabolite of letrozole.

Animals↗
PubMed2004

Association of macrophages, mast cells and eosinophil leukocytes with angiogenesis and tumor stage in non-small cell lung carcinomas (NSCLC).

The association between inflammatory cells, including tumor associated macrophage (TAM), mast cell (MC) and eosinophil leucocyte (EL) densities and angiogenesis, as well as the relation of TAM, MC and EL densities and angiogenesis to tumor stage were investigated in specimens of 63 non-small cell lung carcinoma (NSCLC). Fifteen cases were in stage I, 12 were in stage II, 33 were in stage III and 3 were in stage IV. ELs and MCs were identified by hematoxilen-eosin and toluidine-blue histochemical stains, respectively. TAMs were shown by immunohistochemistry for CD68. Microvessels demonstrated by immunohistochemistry for CD31 were quantified by a stereological method and vascular surface density (VSD) and microvessel number (NVES) were calculated. There was not any statistically significant correlation between tumor's stage and VSD, TAM and EL counts. MC count and NVES were found to be higher in early stages. VSD and NVES were not associated with EL, MC and TAM counts. The lack of consistent correlation of angiogenesis to the stage of disease in this study supports the view that tumor angiogenesis is not a significant prognostic factor in NSCLCs. The absence of correlation between MCs, ELs and TAM counts and angiogenesis and absence of any relation between ELs and TAMs and tumor stage are discordant with the results of some of the previous studies in NSCLCs and in other tumors. The differing results may be due to wide variations in methodologies which were used for demonstration of inflammatory cells and vessels and variations in the degree of activation and complexity of functions of these cells.

Carcinoma, Non-Small-Cell Lung↗
PubMed2004

In vivo occupancy of female rat brain estrogen receptors by 17beta-estradiol and tamoxifen.

Estrogens or antiestrogens are currently used by millions of women, but the interaction of these hormonal agents with brain estrogen receptors (ER) in vivo has not been characterized to date. Our goal was to assess, in vivo, the extent and regional distribution of brain ER occupancy in rats chronically exposed to 17beta-estradiol (E(2)) or tamoxifen (TAM). For that purpose, female ovariectomized Sprague-Dawley rats were implanted with subcutaneous pellets containing either placebo (OVX), E(2), or TAM for 3 weeks. ER occupancy in grossly dissected regions was quantified with 16alpha-[(18)F]fluoroestradiol ([(18)F]FES). Both E(2) and TAM produced significant decreases in radioligand uptake in the brain although the effect of E(2) was larger and more widespread than the effect of TAM. Detailed regional analysis of the interaction was then undertaken using a radioiodinated ligand, 11beta-methoxy-16alpha-[(125)I]iodo-estradiol ([(125)I]MIE(2)), and quantitative ex vivo autoradiography. E(2) treatment resulted in near-complete (86.6 +/- 17.5%) inhibition of radioligand accumulation throughout the brain, while ER occupancy in the TAM group showed a marked regional distribution such that percentage inhibition ranged from 40.5 +/- 15.6 in the ventrolateral part of the ventromedial hypothalamic nucleus to 84.6 +/- 4.5 in the cortical amygdala. These results show that exposure to pharmacologically relevant levels of TAM produces a variable, region-specific pattern of brain ER occupancy, which may be influenced by the regional proportion of ER receptor subtypes. These findings may partially explain the highly variable and region-specific effects observed in neurochemical, metabolic, and functional studies of the effects of TAM in the brain of experimental animals as well as human subjects.

Animals↗
PubMed1998

Effects of tamoxifen, fluphenazine and estradiol on ATP levels in preoptic area and hypothalamic slices from ovariectomized rats.

Tamoxifen, the major adjuvant drug treatment for estrogen-dependent breast cancer, has been shown previously to affect both estrogen-dependent and calcium/calmodulin-dependent pathways. In the current study, we developed an in vitro slice system to study the effects of tamoxifen on ATP levels in hypothalamic (HTH) and preoptic areas (POA) of the rat brain. Baseline data showed that, following a 2-h incubation, HTH and POA slices had comparable ATP levels to hippocampal slices, a system used extensively by researchers examining the metabolic responsiveness of the hippocampal region (HPC) of the brain. HTH-POA slice ATP levels remained steady for 2, 4 and 6 h, but fell to 11% of initial levels by 12 h. Neurons from HTH-POA slices incubated for 4 h appeared healthy and demonstrated robust protein synthesis as measured autoradiographically by incorporation of [3H]leucine. We explored the effects of tamoxifen (TAM), fluphenazine (FLU) and estradiol (E2) on ATP levels in HTH and POA slices. The effects of TAM were complex: a 4-h incubation with 10-6 M TAM led to decreased ATP levels in HTH (but not POA), and a 4-h incubation with 10-8 M led to increased ATP levels in POA (but not HTH); a 15-min exposure to 10-6 M TAM decreased ATP levels in POA (but not HTH) slices, while the exposure of slices to the lower concentration of TAM was without effect in either area. As with higher concentrations of TAM, 4-h incubation with 10-6 M FLU decreased ATP levels in HTH (but not POA), while incubation with E2 did not affect slice ATP levels. These data are consistent with the hypothesis that both TAM and FLU alter ATP levels in HTH slices via calmodulin- or calcium-mediated processes.

Adenosine Triphosphate↗
PubMed2002

Effects of tamoxifen on pulmonary fibrosis after cobalt-60 radiotherapy in breast cancer patients.

BACKGROUND AND PURPOSE: This study was performed to investigate whether the tamoxifen (TAM) induced the development of pulmonary fibrosis after post-mastectomy cobalt-60 (Co-60) irradiation of chest wall and regional lymphatics in patients with breast cancer along with patient age, menopausal status, body weight, observation time and adjuvant chemotherapy regimens. MATERIALS AND METHODS: In this prospective study, 74 patients treated with post-mastectomy adjuvant radiotherapy (RT) and TAM and 37 patients treated with RT were evaluated by axial computerized tomography (CT). CT was first performed before initiation of radiotherapy and TAM treatment. A total of 824 thorax CT sections were evaluated by a radiologist blindly. Comparison of pre-treatment and post-treatment CT sections was used to monitor the development of pulmonary fibrosis. RESULTS: Pulmonary fibrosis developed in 26 of 74 patients who were treated with RT and TAM combination. It was found in five of 37 women treated only with RT. The difference was statistically significant (P<0.01). The median time for the development of pulmonary fibrosis was 8 months in TAM-treated patients whereas it was 10 months in non-TAM-treated patients. Among 111 patients who participated in that study, 65 were in the post-menopausal state and 46 in pre-menopausal state. In the multivariate analysis, the independent prognostic factors were age (P=0.010) and menopausal status (P=0.019). Advanced age and post-menopausal status predisposed to pulmonary fibrosis. The time interval in the development of lung fibrosis and body weight did not significantly influence the results. The time interval which is one independent prognostic factor was found to be associated with lung fibrosis under only-RT group in multivariate analysis (P<0.01). CONCLUSION: TAM treatment during post-mastectomy RT in breast cancer patients significantly increases the risk of the development of lung fibrosis along with the patient age and menopausal status.

Age Factors↗
PubMed2000

Effect of tamoxifen treatment on the endometrial expression of human insulin-like growth factors and their receptor mRNAs.

The effect of tamoxifen (Tam) treatment on the endometrial expression of IGF-I and II/IGF-IR and IIR mRNAs was assessed by measuring the levels of expression of these mRNAs in the endometrial samples of Tam-treated postmenopausal breast cancer patients by RT-PCR assays. The levels of these mRNAs were compared with those in normal endometrium and in Type I and Type II endometrial carcinomas (EC). The promoter-specific transcript profiles of IGF-I and II were also elucidated. The levels of IGF/IGF-R mRNAs in the endometrium from Tam-treated patients were found to be comparable with the high levels of these mRNAs observed in the proliferative and early secretory phase endometrium and in the samples of Type I EC. These results indicate that Tam acts as an estrogen agonist in inducing the endometrial expression of these genes. Tam stimulated transcription from the multiple promoters of IGF-I and II, with the exception of IGF-II P2 promoter, in which case the transcription across exon 4 appeared to be inhibited. The profiles of IGF-I and II transcripts of endometrium from Tam-treated patients were similar to Type I EC but differed considerably from those of Type II EC. These results suggest that the Tam-associated ECs are likely to be similar to type I EC and will therefore have a more favorable prognosis.

Antineoplastic Agents, Hormonal↗
PubMed1998

Comparison of tamoxifen ligands on estrogen receptor interaction with estrogen response elements.

The estrogen receptor (ER) is a ligand-activated transcription factor that binds to specific DNA sequences, estrogen response elements (EREs). Estradiol-liganded ER (E2-ER) binds cooperatively to stereoaligned EREs that are surrounded by naturally-occurring AT-rich sequences with a stoichiometry of one E2-ER dimer per ERE. When ER is bound by 4-hydroxytamoxifen (4-OHT), the active metabolite of the widely used therapeutic antiestrogen tamoxifen (TAM), the receptor binds to EREs with high affinity. However, one molecule of 4-OHT ligand dissociates from the ER dimer apparently during the process of binding to DNA, yielding a stoichiometry of one [3H]4-OHT molecule per ERE. To determine whether DNA-binding induced ligand dissociation is a general property of type I antiestrogens that are not covalently attached to the ER, we examined the interaction of ER liganded by tamoxifen (TAM) with EREs. We demonstrate that TAM-ER binds EREs with lower affinity than E2-ER, 4-OHT-ER, or ER liganded by the covalent antiestrogen tamoxifen aziridine. Unlike E2-ER, both TAM and 4-OHT-ER bind EREs non-cooperatively. Like 4-OHT, TAM appears to dissociate from the liganded ER as the receptor binds EREs. Additionally, partial proteolysis of ERE-bound ER by trypsin revealed different cleavage patterns for E2 versus 4-OHT and TAM. These findings indicate that the behavior of the ER liganded by TAM is generally similar to that of the antiestrogen 4-OHT.

Animals↗