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PubMed2000

Endometrial metastasis from breast cancer in a patient receiving tamoxifen therapy.

Tamoxifen (TAM) is known to be associated with several types of endometrial pathologies, e.g. hyperplasias, polyps and endometrial carcinomas, sometimes of special histologic type. Here we report a rare case of endometrial metastasis from a breast carcinoma (ductal carcinoma) discovered during TAM therapy. This occurrence does not suggest that TAM treatment causes endometrial metastases of breast cancer. However, clinicians should be aware of this possibility and provide patients receiving TAM therapy with close gynecologic follow-up using liberal indications for endometrial biopsies.

Aged↗

PubMed2003

The effect of estradiol in the striatum is blocked by ICI 182,780 but not tamoxifen: pharmacological and behavioral evidence.

Estradiol in the striatum enhances amphetamine (AMPH)- or KCl-stimulated dopamine (DA) release and the pacing of sexual behavior in the female rat. These effects of estradiol in the striatum are rapid, steroid specific and thought to be mediated by a G protein-coupled membrane receptor for estradiol. In the current experiments, we examined whether two antiestrogens, ICI 182,780 (ICI) and tamoxifen (TAM), affect the enhancement by estradiol of (1) AMPH-induced DA release from striatal tissue in vitro, and (2) paced mating behavior in the female rat. The steroidal antiestrogen ICI significantly blocked the effect of estradiol on AMPH-induced striatal DA release. In contrast, the nonsteroidal, triphenylethylene antiestrogen TAM did not block the effect of estradiol, even when a concentration 10 times the concentration of estradiol was delivered to the tissue. Neither of the compounds showed estrogenic action when tested in the absence of estradiol. When implanted into the dorsolateral striatum, ICI inhibited the effect of estradiol on pacing of sexual behavior, while TAM did not. The specific effects of ICI, but not TAM, on striatal DA release and pacing behavior provide further information about the binding site for estradiol in the striatum.

Amphetamine↗

PubMed1997

Combined effect of tamoxifen or interferon-beta and 4-hydroxyphenylretinamide on the growth of breast cancer cell lines.

To improve the effectiveness of 4-hydroxyphenylretinamide (4-HPR), an analogue of retinoic acid used in chemoprevention and treatment of breast cancer, we investigated the effect of concomitant administration of 4-HPR (0.1, 1 microM) and tamoxifen (TAM, 0.1, 1 microM), or 4-HPR and interferon-beta (IFN-beta, 10, 100, 500 IU/ml) on the growth of four cell lines (MCF7, T47D, MDA-MB231 and BT20) characterized by a different steroid receptor profile. A high concentration of 4-HPR caused a significant inhibitory effect not only on the estrogen receptor-positive cell lines (MCF7 and T47D), but also on one (BT20) of the two estrogen receptor-negative cell lines. IFN-beta displayed a dose-dependent inhibitory effect in all cell lines, but it was most evident in MCF7 cells. In all cell lines, the combination of 4-HPR (0.1 microM) and TAM (1 microM) or IFN-beta (500 IU/ml) generally caused additive or synergistic effects. In particular, the finding that in estrogen receptor-negative MDA-MB231 cells 4-HPR (which at 1 microM was singly ineffective) in combination with TAM at 1 microM or any concentration of IFN-beta produced a synergistic effect suggests that the compound could act through a pathway independent of specific receptors for retinoids. Our results indicate that intrinsic characteristics of cells can influence responsiveness to 4-HPR, TAM and IFN-beta, singly or in association, ever within cell lines with similar steroid receptor profiles. Thus, more attention should be payed to the biological characteristics of the single tumor in order to help choose the best combination of drugs to be applied.

Antineoplastic Agents↗

PubMed1986

Hormonal changes during a prolonged tamoxifen treatment in patients with advanced breast cancer.

The effect of tamoxifen (TAM) on the serum levels of sexual hormones and on the sex hormone-binding globulin (SHBG) was investigated in 30 postmenopausal patients with advanced breast cancer. To study the 'prolactin reserve capacity' of the pituitary gland, thyrotrophin-releasing hormone (TRH) and sulpiride-induced prolactin release were measured prior to TAM treatment, then in the 2nd and 8th week of the therapy. The TRH (400 micrograms i.v.)-induced prolactin secretion was significantly suppressed by TAM after an 8-week treatment, but only in responding cases. Maximal prolactin stimulation occurred at the 15th min after TRH injection, being equal to 5,600 +/- 800 mlU/l in cancer patients, and decreasing to 2,400 +/- 150 mlU/l after 8 weeks. TAM did not suppress the sulpiride-inducable prolactin release either in responders or in nonresponders.

Bone Neoplasms↗

PubMed2001

Adenovirus-mediated overexpression of dominant-negative mutant of c-Jun prevents intercellular adhesion molecule-1 induction by LDL: a critical role for activator protein-1 in endothelial activation.

Low density lipoprotein (LDL) induces intercellular adhesion molecule-1 (ICAM-1) gene expression and leads to endothelial cell (EC) leukocyte adhesion. However, the transcriptional mechanism for LDL-induced EC perturbation remains to be fully explained. Activator protein-1 (AP-1) is induced after the exposure of ECs to LDL. In the present study, a regulated adenovirus expressing a dominant-negative mutant of c-Jun (TAM-67) was used to examine the role of AP-1 in the LDL-induced ICAM-1 activation. Overexpression of TAM-67 specifically inhibited AP-1 activation and prevented the LDL-activated surface expression of ICAM-1 protein in human umbilical vein ECs and human coronary artery ECs. Northern analyses and promoter transactivation assays indicated that this effect of TAM-67 was likely mediated through a suppression of the transcriptional regulation of the ICAM-1 gene. Functionally, TAM-67 attenuated leukocyte adherence to ECs in response to LDL. Furthermore, electrophoresis mobility shift assays and site-directed mutagenesis suggested that an AP-1-like motif in the promoter region of the human ICAM-1 gene was a critical cis element for LDL induction. These results, for the first time, provide evidence suggesting that AP-1 is a major regulatory mechanism leading to endothelial activation.

Adenoviridae↗

PubMed2003

Effect of long-term treatment with steroid hormones or tamoxifen on the progesterone receptor and androgen receptor in the endometrium of ovariectomized cynomolgus macaques.

The progesterone receptor (PR) and androgen receptor (AR) belong to the nuclear receptor superfamily. Two isoforms of PR (A and B) have been identified with different functions. The expression of AR, each isoform of PR and their involvement in long-term effects on the endometrium after hormonal replacement therapy (HRT) or tamoxifen (TAM) treatment is not known. The aims of this study were to determine PR(A+B), PRB and AR distribution by immunohistochemistry in the macaque (Macaca fascicularis) endometrium. Ovariectomized (OVX) animals were orally treated continuously for 35 months with either conjugated equine estrogens (CEE); medroxyprogesterone acetate (MPA); the combination of CEE/MPA; or TAM. Treatment with CEE/MPA tended to down-regulate PR in the superficial glands, but increased it in the stroma. TAM treatment increased both the PR and PRB levels in the stroma. Overall, less than 20% of the cells were positive for the PRB isoform and less variation was observed after steroid treatment. AR was found in the stroma, mainly distributed in the basal layer of the endometrium in the OVX and steroid treated groups, but was absent in the TAM treated group. No AR was found in the glandular epithelium. The present data show that long-term hormone treatment affects the PR level, and also the ratio between PRA and PRB in the endometrium.

Animals↗

PubMed1997

Randomized trial of cyclophosphamide, methotrexate, and fluorouracil chemotherapy added to tamoxifen as adjuvant therapy in postmenopausal women with node-positive estrogen and/or progesterone receptor-positive breast cancer: a report of the National Cancer Institute of Canada Clinical Trials Group. Breast Cancer Site Group.

PURPOSE AND METHODS: By the mid 1980s, tamoxifen alone was considered standard adjuvant therapy for postmenopausal women with node-positive, estrogen receptor (ER)- or progesterone receptor (PgR)-positive breast cancer. From 1984 through 1990, 705 eligible postmenopausal women with node-positive, ER- or PgR-positive breast cancer were randomized to a National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) study that compared tamoxifen 30 mg by mouth daily for 2 years (TAM) versus TAM plus chemotherapy with all-intravenous cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, and fluorouracil 600 mg/m2 given every 21 days for eight cycles (CMF). RESULTS: There were no significant differences in overall survival, recurrence-free survival, locoregional recurrence-free survival, or distant recurrence-free survival between the two treatment arms. However, there was significantly greater severe toxicity, which included leukopenia (P < .0001), nausea and vomiting (P < .0001), and thromboembolic events (P < .0001), as well as significantly more mild or greater toxicity, which included thrombocytopenia (P = .04), anemia (P = .02), infection (P = .0004), mucositis (P = .0001), diarrhea (P = .0001), and neurologic toxicity (P = .006), in women who received TAM plus CMF. CONCLUSION: The addition of CMF to TAM adds no benefit and considerable toxicity in this group of women.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

Fertility preservation in breast cancer patients: a prospective controlled comparison of ovarian stimulation with tamoxifen and letrozole for embryo cryopreservation.

PURPOSE: To develop safe ovarian stimulation methods to perform in vitro fertilization (IVF) in breast cancer patients who wish to preserve their fertility via embryo cryopreservation before chemotherapy. PATIENTS AND METHODS: Sixty women (age range, 24 to 43 years) with breast cancer were prospectively studied. Twenty-nine patients underwent 33 ovarian stimulation cycles with either tamoxifen 60 mg/d alone (Tam-IVF) or in combination with low-dose follicle-stimulating hormone (TamFSH-IVF) or letrozole 5 mg in combination with FSH (Letrozole-IVF). After IVF, all resultant embryos were cryopreserved to preserve fertility. Recurrence rates were compared with controls (n = 31) who elected not to undergo IVF. RESULTS: Compared with Tam-IVF, both TamFSH-IVF and Letrozole-IVF patients had greater numbers of follicles (2 +/- 0.3 v 6 +/- 1 and 7.8 +/- 0.9, respectively; P < .0001), mature oocytes (1.5 +/- 0.3 v 5.1 +/- 1.1 and 8.5 +/- 1.6, respectively; P < .001), and embryos (1.3 +/- 0.2 v 3.8 +/- 0.8 and 5.3 +/- 0.8, respectively; P < .001). Peak estradiol (E2) levels were lower with Letrozole-IVF and Tam-IVF compared with TamFSH-IVF. After 554 +/- 31 days (range, 153 to 1,441 days) of follow-up, cancer recurrence rate was similar between IVF and control patients (three of 29 v three of 31 patients, respectively; hazard ratio, 1.5; 95% CI, 0.29 to 7.4), and this estimate was not affected by cancer stage. CONCLUSION: The combination of low-dose FSH with tamoxifen (TamFSH-IVF) or letrozole (Letrozole-IVF) results in higher embryo yield compared with Tam-IVF. Recurrence rates do not seem to be increased, but the letrozole protocol may be preferred because it results in lower peak E2 levels.

Adult↗

PubMed1986

Modulation of aromatase activity in human endometrial stromal cells by steroids, tamoxifen and RU 486.

The regulation of aromatase activity (AA) in human endometrial stromal cells by various steroids was studied in primary cell culture. Various progestins, but not androgens or glucocorticoids, stimulated AA. Medroxyprogesterone acetate (MPA) was the most potent progestin. Estrogen (E) alone did not change the activity but it potentiated the stimulation of AA by progestin. Biphasic regulation of AA by progestin was noted in both time- and dose-dependent manners. Endometrial AA was stimulated by MPA and reached the maximum rate between 2-5 days of incubation with subsequent decline of AA in prolonged culture. When stromal cells were treated with MPA (0.03 to 30 microM) for 3 days, AA was increased over the control at all the concentrations tested. The maximum was found at doses between 0.1-1 microM. The activities reduced steadily from the maximum stimulation to less than 50% when the concentration of MPA increased from 1-30 microM. In addition, initial treatment of stroma cells with MPA (1-3 days) resulted in further increase of activity after progestin withdrawal. The enhancement of the induction of AA by E did not alter the biphasic pattern regulated by progestin alone, i.e. E enhanced both the stimulation and the decay of AA. The time study of the effect of E showed that enhancement of AA required at least 10 h of incubation of E with MPA conditioned cells. The effect of E is dose dependent between 0.04-40 nM and shows the greatest effect in the presence of MPA between 0.01-1 microM. The optimal concentrations of E and progestin that stimulate AA in culture are similar to the plasma concentrations after pregnancy, suggesting that the physiological function of the endometrial aromatase is at the time of decidualization. The effects of antiprogestin, Ru 486, and antiestrogen, tamoxifen (TAM), on AA were studied. Ru 486 or TAM alone did not alter AA. Ru 486 inhibited the MPA stimulated AA in a dose-dependent manner suggesting that the effect of progestin may be mediated through a receptor mechanism. Enhancement, but no inhibitory effect, was observed when cells were treated with TAM + MPA and TAM + MPA + E. The effectiveness of Ru 486 to inhibit the induction of AA in endometrial cells may be of primary importance for contraception.

Adult↗

PubMed1994

Estrogen and androgen differentially modulate the growth-associated protein GAP-43 (neuromodulin) messenger ribonucleic acid in postnatal rat brain.

The level of expression of the gene encoding GAP-43, a protein implicated in neurite outgrowth and motility, is sexually dimorphic in the postnatal brain and modulated by testosterone (T). To determine which metabolite of T modulates the expression of GAP-43 in the postnatal brain, the present study investigated the effect of estrogen and androgen receptor antagonists, tamoxifen (TAM) and cyproterone acetate (CA), and agonists, diethylstilbestrol (DES) and dihydrotestosterone (DHT). On postnatal day 1, male rats were injected sc daily with oil, TAM, or CA, whereas additional female pups were treated with oil, DES, or DHT. On postnatal day 6, brains were collected and 16-micron cryostat sections processed and hybridized with a 35S-labeled antisense riboprobe complementary to GAP-43 messenger RNA (mRNA). A comparison of hybridization signal in the cerebral cortex, bed nucleus of the stria terminalis, and medial preoptic nucleus demonstrated that the level of GAP-43 mRNA in males was significantly higher than in females. However, when male pups were injected with CA, a female-like level of GAP-43 mRNA was measured in the cerebral cortex. The low level of GAP-43 hybridization signal in the female cortex was markedly increased when females were treated with DHT. In contrast, the level of GAP-43 mRNA in the male medial preoptic nucleus was attenuated after treatment with TAM, whereas the level in the female was augmented with DES. Interestingly, the level of GAP-43 mRNA in the bed nucleus was reduced when males were treated with either TAM or CA and augmented when females were administered either DES or DHT. The results of these studies indicate that the effects of T on GAP-43 mRNA levels in the postnatal brain are modulated by estrogen- and androgen receptor-mediated events in a region-specific manner.

Androgens↗

PubMed1999

Estrogen receptor beta activates the human retinoic acid receptor alpha-1 promoter in response to tamoxifen and other estrogen receptor antagonists, but not in response to estrogen.

Human estrogen receptor-alpha (hERalpha) or -beta (hERbeta) transfected into Hep G2 or COS1 cells each responded to estrogen to increase transcription from an estrogen-responsive element (ERE)-driven reporter vector with similar fold induction through a classical mechanism involving direct receptor binding to DNA. ER antagonists inhibited this estrogen induction through both hERalpha and hERbeta, although raloxifene was more potent through ERalpha than ERbeta, and tamoxifen was more potent via ERbeta than ERalpha. We have shown previously that estrogen stimulated the human retinoic acid receptor-alpha-1 (hRARalpha-1) promoter through nonclassical EREs by a mechanism that was ERalpha dependent, but that did not involve direct receptor binding to DNA. We show here that in contrast to hERalpha, hERbeta did not induce reporter activity driven by the hRARalpha-1 promoter in the presence of estrogen. While hERbeta did not confer estrogen responsiveness on this promoter, it did elicit transcriptional activation in the presence of 4-hydroxytamoxifen (4-OH-Tam). Additionally, this 4-OH-Tam agonist activity via ERbeta was completely blocked by estrogen. Like ERalpha, transcriptional activation of this promoter by ERbeta was not mediated by direct receptor binding to DNA. While hERalpha was shown to act through two estrogen-responsive sequences within the promoter, hERbeta acted only at the 3'-region, through two Sp1 sites, in response to 4-OH-Tam. Other ER antagonists including raloxifene, ICI-164,384 and ICI-182,780 also acted as agonists through ERbeta via the hRARalpha-1 promoter. Through the use of mutant and chimeric receptors, it was shown that the 4-OH-Tam activity via ERbeta from the hRARalpha-1 promoter in Hep G2 cells required the amino-terminal region of ERbeta, a region that was not necessary for estrogen-induced ERbeta activity from an ERE in Hep G2 cells. Additionally, the progesterone receptor (PR) antagonist RU486 acted as a weak (IC50 >1 microM) antagonist via hERalpha and as a fairly potent (IC50 approximately 200 nM) antagonist via hERbeta from an ERE-driven reporter in cells that do not express PR. Although RU486 bound only weakly to ERalpha or ERbeta in vitro, it did bind to ERbeta in whole-cell binding assays, and therefore, it is likely metabolized to an ERbeta-interacting compound in the cell. Interestingly, RU486 acted as an agonist through ERbeta to stimulate the hRARalpha-1 promoter in Hep G2 cells. These findings may have ramifications in breast cancer treatment regimens utilizing tamoxifen or other ER antagonists and may explain some of the known estrogenic or antiestrogenic biological actions of RU486.

Animals↗

PubMed1995

[The diverse effects of hormonal therapeutic agents on the proliferations of human breast cancer cell lines, MCF-7 and its variants].

The author established three variant cell lines which were proliferative in the serum-free medium. These three cell lines were derived from MCF-7, a human breast cancer cell line. These 3 variants (MCF-S1, MCF-S2 and MCF-S3) proliferate estrogen (E2)-dependently, but the amounts of E2 receptor and progesterone receptor in the cells are different from each other among the variants. The author compared the effects of hormonal therapeutic agents, tamoxifen (TAM), 3-hydroxytamoxifen (3-OH-TAM), toremifene (TORE), and medroxyprogesterone acetate (MPA) on MCF-7 and the established variant cells. Although TAM showed little effect on the growth of any cell lines in the absence of E2, it considerably inhibited the growth of MCF-S2 cells and MCF-7 cells in the presence of 10(-10)M E2. TORE also provided no inhibitory effect at less than 10(-7)M concentration on any cells in the absence of E2, but it dose-dependently inhibited DNA synthesis of MCF-S2 cells in the presence of E2. On the other hand, although 3-OH-TAM markedly inhibited the growth of any cell lines at a concentration of less than 10(-6)M in the presence of E2, it dose-dependently inhibited the DNA synthesis of any cell lines in the absence of E2, and the effect was remarkable in the case of MCF-S2 or MCF-S3. MPA showed a tendency to increase the proliferation of any cells in the absence of E2, conversely in the presence of E2, and it slightly inhibited DNA synthesis at concentrations of over 10(-8)M. These results suggest that the effect of hormonal agents on breast cancer cells may depend on either hormonal levels or the characteristics of the cancer cells. The effect of the hormonal agents are diverse, and a hormonal agent which does not work well on one cancer cell population may work well on another population.

Breast Neoplasms↗

PubMed1999

The relationship of host immune cells, cytokine and nitric oxide production to tumor cells in ovarian carcinoma.

AIMS: This brief review focuses on the current understanding of the complex relationship of tumor-associated mononuclear cells (TAMs) with neoplastic cells, summarizing their immunological efficiency, cytokine profile and production of nitric oxide (NO) in the tumor microenvironment, with current insights on how this might affect tumor growth. DATA SOURCE: Data was obtained through Medline from articles indexed during the last 10 years. The main key words used in the research were: cancer, ovarian cancer, cytokine, nitric oxide (NO), mononuclear cell, lymphocyte, macrophage. SELECTION OF STUDIES AND DATA COLLECTION: 30 studies were reviewed, which contained data regarding the production of cytokines and NO by TAMs or malignant cells, and tried to establish a correlation between these mediators and tumor growth, especially in ovarian carcinoma. DATA SUMMARY: TAMs consist mainly of macrophages and T lymphocytes which present lower proliferative indices and cytotoxicity compared to autologous blood monocytes, although they are able to release various cytokines. The profile of cytokine expression could help to explain both the immunological impairment observed in patients with advanced carcinoma diseases and the potential of TAMs to exert antitumor activity, which makes these cells an attractive target for therapeutic intervention. NO is also produced in the tumor microenvironment. Several reports in animals suggest a tumoricidal role for NO, but in human tumors its role has not been well-established and may change during tumor progression.

Cytokines↗

PubMed2005

Cytotoxic and antiproliferative activity of the single agent epirubicin versus epirubicin plus tamoxifen as primary chemotherapy in human breast cancer: a single-institution phase III trial.

This study was designed to address whether simultaneous primary chemo-hormonal therapy provides additional activity compared with chemotherapy alone in breast cancer patients with operable or locally advanced disease. Between January 1997 and January 2002, 211 consecutive patients with T2-4, N0-1, M0 breast cancer were randomized to receive either epirubicin alone (EPI) or epirubicin plus tamoxifen (EPI-TAM). Ki67 expression was evaluated immunohistochemically in tumor specimens obtained before chemotherapy by incision biopsy and at definitive surgery. Tumor shrinkage of >50% was obtained in 76% of patients randomized in the EPI arm and 81.9% of patients randomized in the EPI-TAM arm (not significant). The corresponding rates of clinical and pathological complete response were 20.2 and 21.9% (not significant), and 4.8 and 6.7% (not significant), respectively. Pathologically complete response was more frequently observed in estrogen receptor (ER)-negative (ER-) tumors (P=0.04) and correlated with elevated baseline Ki67 expression (P<0.01). Both EPI and EPI-TAM treatments resulted in a significant reduction in Ki67 expression, either in overall patients (P=0.000) or in patients with ER+ breast cancer (P=0.000). The reduction in Ki67 immunostaining in the EPI-TAM arm was greater than in the EPI arm, leading to a lower Ki67 expression at post-operative residual histology (P=0.0041). The addition of tamoxifen to epirubicin chemotherapy did not improve the response rate but led to a significantly higher reduction in the Ki67 expression. Baseline elevated Ki67 expression and the ER- status were both associated with a greater chance of obtaining a pathological complete response at residual histology.

Adult↗

PubMed1996

Stimulation of creatine kinase specific activity in human osteoblast and endometrial cells by estrogens and anti-estrogens and its modulation by calciotropic hormones.

We have previously demonstrated sex-specific stimulation of creatine kinase specific activity (CK) in bone cells both in vivo and in vitro, in primary culture cells derived from rat and human bone and in established human bone-derived cell lines. We found that the female-derived cell line, SaOS-2, responded to 17 beta-estradiol (E2) by increased CK specific activity. The effects of E2 on the CK activity in SaOS-2 cells was inhibited by 100-fold excess of 4-hydroxytamoxifen (Tam) as well as by the other antiestrogen, ICI 164,384. Tam by itself had some stimulatory effect whereas ICI 164,384 showed no estrogenic activity. We also demonstrated the estrogenic-like effect of another anti-estrogen, raloxifene (Ral), which is agonist only in the SaOS-2 osteoblast-like cells but not in the human endometrial, Ishikawa cell line. Ishikawa cells respond to E2 and to Tam by increased CK activity. In both osteoblasts and endometrial cell lines, Ral and Tam were inhibitory in the presence of E2. The effects of E2 on SaOS-2 cells are at least partially mediated by the estrogen receptor (ER) at the level of transcription as demonstrated by transient transfection experiments using the human creatine kinase promoter chloramphenicol acetyltransferase in these cells. Pretreatment of SaOS-2 with calcitropic hormones, either 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) or human parathyroid hormone (1-34) (hPTH(1-34)) increased the stimulation of CK by E2 by 40-60% relative to E2 alone and significantly increased the sensitivity of the cells to E2 by lowering the effective hormonal dose needed for stimulation of CK by E2 by 100-fold. This stimulatory effect of pretreatment of the cells with 1,25(OH)2D3 was due to a 2.5-fold increase in the level of ER expression as measured directly by enzyme immunoassay in the SaOS-2/1 subline. The increase in the responsiveness to E2 by hPTH(1-34) was not due to an increase in ER level in the cells. We can conclude that in cell cultures as in vivo, Ral shows different effects depending on the cell type, namely estrogenic-like activity in skeletal cells but not in uterine cells. We can also conclude that as with rat-derived cells, in bone cells derived from human bone 1,25(OH)2D3 increased the sensitivity to E2 due to an increase in the number of ER in the cells, whereas PTH(1-34) augmented the response to E2 without increasing ER, by another, as yet unknown, mechanism. These studies suggest that the treatment of pathological bone disorders may be improved by combined hormone therapy.

Calcitriol↗

PubMed1997

Activation of estrogen receptor-mediated gene transcription by IGF-I in human breast cancer cells.

Estrogen and IGF-I are potent mitogens for most breast cancer cell lines, and although their signaling pathways contrast, there is considerable interaction between them. Recent evidence indicating that IGF-I can alter estrogen receptor (ER) action led us to investigate whether an inhibitor of IGF-I action. IGF-binding protein-1 (IGFBP-1), could affect transcriptional activation of ER. First, we confirmed that tamoxifen (TAM) could inhibit IGF-I-mediated proliferation of MCF-7 cells. Although TAM can increase IGFBP-3 expression in MCF-7 cells, and this binding protein has been shown to be able to inhibit IGF action, TAM had no effect on IGF-I-stimulated tyrosine phosphorylation of IGF-I receptor or the downstream signaling molecule, insulin receptor substrate-1. Therefore, to confirm that IGF-I was affecting transcriptional activation of ER, we utilized a gene reporter assay using a single consensus estrogen response element (ERE-tk-luc) upstream of luciferase. As expected, estradiol (E2; 1nM) increased transcriptional activation three- to fivefold from the ERE in three ER-positive breast cancer cell lines (MCF-7, ZR-75 and T47D). A 2.5-to 4-fold increase was also seen with IGF-I (5 nM). TAM (1 microM) effectively blocked activation by E2 and IGF-I, indicating disruption of ER-mediated transcription. As expected, human recombinant IGFBP-1 (80 nM) completely inhibited IGF-I-mediated activation of ER, however, IGFBP-1 also caused a significant decrease in E2-mediated activation. We also noticed that IGF-I increased the activity of all plasmids that we cotransfected including TATA-luc, SV40-luc and pGL Basic. This effect was post-transcriptional, as it was not affected by actinomycin D (2 micrograms/ml), while we were able to completely inhibit E2-mediated transcriptional activation of ERE-tk-luc. Unlike the complete inhibition of ER-mediated transcriptional activation by actinomycin D, IGF-I-mediated transactivation was reduced by only 50%, indicating that the activation by IGF-I represented both transcriptional and post-transcriptional effects. This study confirmed that IGF-I can cause transcriptional activation of endogenous ER in human breast cancel cells, and inhibition of ER action by IGFBP-1 suggests that IGF-1 signaling may be necessary for maximal ER activation.

Breast Neoplasms↗

PubMed1999

Morphometric studies of neonatal estrogen imprinting in the mature mouse prostate.

Estrogens play an important role in prostate physiology and neonatal exposure to estrogens has profound effects on the mature structure and hormonal sensitivity of rodent prostate. We aimed to determine the long-term effects of neonatal estrogens on the ductal architecture, morphology and hormonal sensitivity of the mature mouse prostate. Newborn mice (day 1-2) were administered a single injection (s.c.) of estrogens (estradiol benzoate (EB), diethylstilbestrol (DES)) with or without concomitant anti-estrogens (tamoxifen (TAM) or ICI 182 780 (ICI)) TAM or ICI alone, GnRH-antagonist (GnRH-A) or vehicle. At 7 weeks of age, ventral prostates (VP) were microdissected to estimate branch tip numbers and processed for stereologic analysis of volume fractions and diameters of various tissue components. Estrogens induced permanently reduced branching morphogenesis leading to reduced VP weights and these effects were fully reproduced by GnRH-A, consistent with an indirect effect. Stereologically, neonatal estrogens induced epithelial and stromal hyperplasia and significantly reduced (P<0.05) the diameters of VP glandular tubules and lumen compared with controls and these regressive effects were not reversed either by TAM or ICI. These studies confirm that a single neonatal dose of both DES and EB produces imprinting in the mature mouse prostate and indicate that neonatal estrogen effects involve both direct as well as indirect effects. In addition, both TAM and ICI act as partial agonists to the estrogen receptor in the ventral prostate of neonatal mouse.

Animals↗

PubMed1988

Postmastectomy irradiation in high-risk breast cancer patients. Present status of the Danish Breast Cancer Cooperative Group trials.

All pre- and postmenopausal high-risk breast cancer patients in the protocols DBCG 77 of the Danish Breast Cancer Cooperative Group received postmastectomy irradiation before randomization to either adjuvant systemic therapy or no such treatment. The actuarial loco-regional recurrence rate at 9 years was 6-17%, with the lowest rate in patients who also received additional adjuvant chemotherapy or tamoxifen. In a subsequent study (DBCG 82) the role of postmastectomy irradiation together with systemic treatment was evaluated in high-risk patients. Pre- and menopausal patients were randomized to postmastectomy irradiation + CMF (cyclophosphamide, methotrexate, 5-fluorouracil), CMF alone or CMF + TAM (tamoxifen). Postmenopausal patients were randomized to postmastectomy irradiation + TAM, TAM or CMF + TAM. At 4 years the loco-regional recurrence rate was significantly lower in the irradiated patients (5-7% vs. 23-33%). Further, disease-free survival was significantly improved in both pre- and postmenopausal irradiated patients compared with those who had only systemic treatment. At present, there are no significant differences between survival in the treatment groups. Thus, adjuvant systemic treatment alone (chemotherapy and/or tamoxifen) did not prevent loco-regional recurrences in high-risk patients after mastectomy and axillary lymph node sampling. However, a longer observation time is necessary to evaluate the consequence of primary optimal loco-regional tumour control in high-risk breast cancer patients with respect to survival.

Antineoplastic Combined Chemotherapy Protocols↗