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Query: UMLS:C0276241 (MCF)
 28,353 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Non-steroidal antioestrogens, such as tamoxifen, inhibit the growth of human breast cancer cells. The experiments described here compare and contrast the efficacy of tamoxifen and the 'pure' antioestrogen, ICI 164384, on the inhibition of proliferation of MCF-7 cells. Previous studies have shown that ICI 164384 has a greater maximal inhibitory effect than conventional antioestrogens on the growth of MCF-7 cells. Both types of compound block progression of cells through the cell cycle in the early G1 phase. These studies have been extended to measure the population distribution of antioestrogen-treated cells by the use of two-parameter flow cytometry. ICI 164384 proved to be more effective than tamoxifen in decreasing the proportion of actively growing cells in an asynchronous population. In cells grown in the complete absence of exogenous oestrogens, growth was stimulated by oestradiol, insulin, insulin-like growth factor-I (IGF-I) or transforming growth factor-alpha (TGF-alpha). The potent metabolite of tamoxifen, trans 4'-hydroxytamoxifen (4'-OHT), alone also stimulated growth, whereas ICI 164384 did not. Oestradiol and insulin added together demonstrated a clear synergistic enhancement of cell growth. Correspondingly, the stimulatory effect of 4'-OHT on growth was magnified in the presence of insulin, and a combination of ICI 164384 with insulin revealed a much weaker stimulatory action of the 'pure' antagonist. For both compounds the interaction with insulin was complex and characterized by a bell-shaped dose-response curve. However, for 4'-OHT at all concentrations in the range 1 pM-1 microM in the presence of insulin, cell numbers were greater than in cultures exposed to insulin alone. This was not the case for ICI 164384 which suggested that differences in efficacy may be due to interactions between oestrogen and growth factor-mediated mechanisms. Furthermore, ICI 164384 was more effective in inhibiting the action of IGF-I and TGF-alpha alone or in combination, although both antioestrogens produced a partial blockade of growth factor responses in the complete absence of oestradiol. It is concluded that the difference in efficacy between partial agonist and 'pure' antagonist antioestrogens to inhibit growth in vitro is consistent with the difference in the pharmacological profile of these compounds. The absence of stimulatory activity of ICI 164384 is of particular significance in reducing to a minimum the synergistic interaction between oestrogens and insulin.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of antioestrogens on the proliferation of MCF-7 human breast cancer cells. 266 80

The influence of paracrine factors secreted by the hormone independent breast cancer cell line MDA-MB-231 on the growth of the hormone dependent breast cancer cell line MCF-7 was examined in the absence of estradiol and in the presence of inhibitory concentrations of antiestrogens. MDA-MB-231 cells were grown on transwell membranes and co-cultured with MCF-7 cells (50,000) plated in 6-well tissue culture dishes. Growth was maximally increased (80%) when MCF-7 cells were grown in the presence of 150,000 or more MDA-MB-231 cells for 4 days. The non-steroidal antiestrogens tamoxifen (10(-10) to 10(-6) M) and 4-hydroxytamoxifen (10(-11) to 10(-7) M), the steroidal antiestrogens ICI 164384 (10(-10) to 10(-6) M) and Ru39411 (10(-11) to 10(-7) M) all inhibited estradiol (10(-11) M) stimulated MCF-7 cell growth in a dose related manner when cultured for 4 days. However, the paracrine stimulation of MCF-7 cells produced by co-culture with 250,000 MDA-MB-231 cells was not inhibited by any of these antiestrogens. These data suggest that in heterogeneous tumors, paracrine factors from hormone independent cells may reverse the growth inhibitory action that antiestrogens have on estrogen-dependent breast cancer cell growth.
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PMID:The paracrine stimulation of MCF-7 cells by MDA-MB-231 cells: possible role in antiestrogen failure. 270 4

Tamoxifen and other structurally related nonsteroidal antiestrogens possess properties in addition to their estrogen antagonist activity including inhibition of both calmodulin and protein kinase C. The present studies were designed to test whether the estrogen-reversible (estrogen receptor mediated) and estrogen-irreversible effects of nonsteroidal antiestrogens on cell cycle progression in vitro were mediated at the same or different points within the cell cycle and if the estrogen-irreversible effects coincided temporally with that of a calmodulin antagonist, R24571. Initial experiments investigated the effects of ICI 164384, a pure estrogen antagonist, on proliferation kinetics in asynchronous cultures of MCF-7 human breast cancer cells. At concentrations greater than 1 nM ICI 164384 significantly reduced growth rate while at greater than or equal to 50 nM, ICI 164384 completely arrested growth after the first 24 h of exposure. Concentrations up to 5 microM failed either to cause more profound effects on growth or induce cytotoxicity. Growth inhibition was associated with a decrease in the proportion of S phase cells and an accumulation of cells in G1 phase, and was completely reversed by the simultaneous addition of equimolar estradiol. In order to identify the points of action within the cell cycle of ICI 164384, and the estrogen-reversible and estrogen-irreversible components of the nonsteroidal estrogen antagonist, hydroxyclomiphene, and the calmodulin antagonist, R24571, experiments were undertaken with MCF-7 cells synchronized by mitotic selection. The mean point of action was assessed by delaying addition of the drugs for increasing time periods following mitotic selection and using DNA flow cytometry to determine the proportion of the population affected by drug administration at a specific time within G1 phase. These studies showed that sensitivity to ICI 164384 was restricted to the early part of G1 phase and that the mean time of action was 4.9 h after the beginning of G1 for this pure estrogen antagonist. The mean times of action of the estrogen-reversible (4.1 h into G1 phase) and estrogen-irreversible (4.1 h) mechanisms of action of hydroxyclomiphene, and R24571 (4.0 h), all appeared to be within a similar time frame in early to mid G1 phase. It is concluded that ICI 164384 inhibits breast cancer cell proliferation by inducing a transition delay in G1 phase and that the point of action of this pure estrogen antagonist in early G1 phase is indistinguishable temporally from that of nonsteroidal antiestrogens and calmodulin antagonists.
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PMID:Points of action of estrogen antagonists and a calmodulin antagonist within the MCF-7 human breast cancer cell cycle. 270 27

A potential mechanism is described by which a growth factor may prevent the action of antiestrogens or reactive the growth of hormone-responsive breast carcinoma in patients undergoing tamoxifen (TAM) treatment. Epidermal growth factor (EGF)-stimulated growth (10(-8) M EGF) was assayed in the MCF-7 breast cancer cell line in the presence of various concentrations (10(-10) to 10(-6) M) of three antiestrogens, 4-hydroxytamoxifen (OH TAM), TAM and ICI 164384. In each case, the EGF-stimulated increases in DNA were not inhibited by the antiestrogen. OH TAM and ICI 164384 inhibited estradiol (E2) stimulated cell proliferation in a dose-related fashion. However, in the presence of both E2 and EGF, these two antiestrogens inhibited E2 effects only; EGF promotion of growth was unaffected. Pretreatment of MCF-7 cells for 2 days with either OH TAM or ICI 164384 did not inhibit EGF-induced increases in cell proliferation. We propose that eventual antiestrogen therapeutic failure may be caused by the paracrine influences of growth factors from neighboring cells.
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PMID:Contrasting ability of antiestrogens to inhibit MCF-7 growth stimulated by estradiol or epidermal growth factor. 278 1

The oestrogenic and antioestrogenic properties of some novel 7 alpha-alkyl amide derivatives of 17 beta-oestradiol have been measured in rats and mice. The compound ICI 164384 was devoid of oestrogenic activity in the uterus and vagina of both species and on the hypothalamic-pituitary axis of the rat. ICI 164384 blocked completely the uterotrophic action of exogenous and endogenous oestradiol and of the partial agonist antioestrogens typified by tamoxifen. Unlike tamoxifen ICI 164384 did not promote premature vaginal opening in neonatal rats. The affinity of ICI 164384 for the rat uterus oestrogen receptor was substantially greater than that of tamoxifen. In MCF-7 and ZR-75-1 breast cancer cells in tissue culture ICI 164384 was a more potent inhibitor of cell growth than tamoxifen and growth inhibition was reversed by oestradiol. The properties of ICI 164384 satisfy many of the criteria which define pure antioestrogens.
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PMID:Novel antioestrogens without partial agonist activity. 319 10

Genetic and environmental factors can modulate the level of sensitivity to various hormones, including estrogens. Enhanced sensitivity to estradiol (E2) has been demonstrated in several biological conditions, such as in sheep during the nonbreeding season, in untreated patients with Turner's syndrome, and in the prepubertal state in normal girls. We postulated that secondary responses to hormonal therapy in patients with breast cancer could also result from enhanced E2 sensitivity, developing as an adaptive mechanism to E2 deprivation. The present study used the MCF-7 human breast cancer cell line as a model system to test the concept that enhanced sensitivity to E2 may occur as a result of adaptation to low E2 levels. After depriving MCF-7 cells of estrogens in tissue culture medium for periods of 1-6 months, we established conditions under which replication could be stimulated maximally by 10(-14)-10(-15) mol/L E2. In contrast, wild-type cells not exposed to estrogen deprivation required 10(-10) mol/L E2 to grow at the same rate. Further, the concentration of the antiestrogen, ICI 164384, needed to inhibit growth by 50% in estrogen-deprived cells was much lower than that required in wild-type cells (i.e. 10(-15) vs. 10(-9) mol/L). Nude mice implanted with these estrogen-deprived cells demonstrated an earlier appearance of palpable tumors in response to E2 than animals bearing wild-type cells. Reexposure to 10(-10)-10(-9) mol/L E2, either in vivo or in vitro, returned these cells to the level of estrogen sensitivity observed in wild-type cells. Taken together, these observations suggest that breast cancer cells can adapt to low levels of estrogens by enhancing their sensitivity to E2.
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PMID:Estrogen deprivation causes estradiol hypersensitivity in human breast cancer cells. 755 75

The level of oestrogen-responsive gene expression in breast tumours has been proposed as a predictor of the response of the tumour to endocrine (anti-oestrogen) therapy. We demonstrate that different oestrogen-responsive genes may differ in their responses to other hormones. pLIV-1 and pS2 are two oestrogen-regulated genes that are expressed in the MCF-7 human breast cancer cell line. We show that pLIV-1 mRNA, but not pS2 mRNA, is also induced, to a lesser extent, by progesterone, 5 alpha-dihydrotestosterone and dexamethasone. For pLIV-1, combinations of these hormones with oestradiol and with the pure anti-oestrogen, ICI 164384, indicate that the mechanism of its response to these other steroid hormones is clearly separable from its response to oestrogen. Such behaviour in breast tumours in vivo could explain the lack of absolute correlation between marker gene expression and anti-oestrogen sensitivity and between the expression of individual marker genes.
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PMID:Oestrogen-induced genes, pLIV-1 and pS2, respond divergently to other steroid hormones in MCF-7 cells. 764 56

Estradiol levels in breast tumors from post-menopausal women are similar to those in pre-menopausal women even though plasma estrogens are much lower after the menopause. In situ estrogen production by the tumor provides a potential means of maintaining high estradiol levels in post-menopausal breast cancer tissue. The estrone sulfatase pathway has been proposed as the mediator of in situ estrogen production. A number of studies suggest that estrone sulfate may be converted into estradiol in breast tumors via the catalytic activity of estrone sulfatase and 17 beta-hydroxysteroid dehydrogenase. However, these studies used pharmacologic levels of estrogen sulfates and have not shown that physiologic levels can support biologic effects. Accordingly, the present study examined the dose relationship of estrone sulfate to a variety of biologic endpoints in MCF-7 breast cancer cells in culture. These cells converted physiologic concentrations of estrone sulfate to quantities of free estradiol capable of stimulating cell growth. Under these conditions, the nuclear steroids observed were free estrone and estradiol. Increase in cell number after 6 days of exposure to steroid required 100 nM estrone sulfate. However, S-phase, a more sensitive measure of cell proliferation, was stimulated by 0.1 nM estrone sulfate, a clearly physiologic concentration. Stimulation of estrogen-dependent protein markers such as pS2 and progesterone receptor required much higher concentrations of estrone sulfate. These effects were mediated through the estrogen receptor since the pure anti-estrogen, ICI 164384, blocked all effects produced by estrone sulfate. While it has been suggested that anti-estrogens may partly exert their effects by inhibition of sulfatase and 17 beta-hydroxysteroid dehydrogenase, this did not occur under our experimental conditions. These data provide evidence of the relevance of the estrone sulfatase pathway since biologic effects can be demonstrated in response to physiologic concentrations of estrone sulfate.
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PMID:Estrone sulfate promotes human breast cancer cell replication and nuclear uptake of estradiol in MCF-7 cell cultures. 847 38

The response of two endogenous, estrogen-induced genes, LIV-1 and pS2, to growth factor stimulation of MCF-7 cells was examined. Epidermal growth factor (EGF), transforming growth factor alpha (TGF alpha) and insulin-like growth factor-1 (IGF-1) were each able to induce an increase in the two mRNAs in the absence of estradiol, and their effects were additive to that of an optimally inducing concentration (10(-8) M) of the hormone. Induction by EGF and TGF alpha, but not by IGF-1, were also additive to induction by a saturating concentration (2 microg/ml) of insulin. TGFbeta, an antimitogenic growth factor for MCF-7 cells, did not induce LIV-1 or pS2 mRNA but inhibited induction by estradiol. Increases in mRNA were shown to reflect increases in specific gene transcription. Induction by growth factors, but not by estradiol, was dependent upon protein synthesis. Induction by both growth factors and estradiol was inhibited by the pure antiestrogen, ICI 164384 (ICI), and by the mixed agonist/antagonist, tamoxifen. Despite differences in patterns of expression in vivo and in vitro, both LIV-1 and pS2 appeared to be responsive to growth factors via a mechanism distinct from that of estradiol but requiring the estrogen receptor.
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PMID:Interaction between estradiol and growth factors in the regulation of specific gene expression in MCF-7 human breast cancer cells. 921 17

Since estrogens play a predominant role in the development and growth of human breast cancer, antiestrogens represent a logical approach to the treatment of this disease. The present study compares the effects of the novel nonsteroidal anti-estrogen EM-800 and related compounds with those of a series of anti-estrogens on basal and 17 beta-estradiol (E2)-induced cell proliferation in human breast cancer cell lines. In the absence of added E2, EM-800 and related compounds failed to change basal cell proliferation, thus showing the absence of intrinsic estrogenic activity in the ER-positive T-47D, ZR-75-1 and MCF-7 cell lines. The stimulation of T-47D cell proliferation induced by 0.1 nM E2 was competitively blocked by a simultaneous incubation with EM-652, EM-800, OH-tamoxifen, OH-toremifene, ICI 182780, ICI 164384, droloxifene, tamoxifen and toremifene at apparent Ki values of 0.015, 0.011-0.017, 0.040-0.054, 0.043, 0.044, 0.243 and 0.735 nM, approx. 10 nM and > 10 nM, respectively. Similar data were obtained in ZR-75-1 and/or MCF-7 cells. Moreover, EM-652 was 6-fold more potent than OH-Tamoxifen in inhibiting the proportion of cycling MCF-7 cells. Our data show that EM-800 and EM-652 are the most potent known antiestrogens in human breast cancer cells in vitro and that they are devoid of the estrogenic activity of OH-tamoxifen and droloxifene suggested by stimulation of cell growth in the absence of estrogens in ZR-75-1 and MCF-7 cells.
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PMID:Characterization of the effects of the novel non-steroidal antiestrogen EM-800 on basal and estrogen-induced proliferation of T-47D, ZR-75-1 and MCF-7 human breast cancer cells in vitro. 933 16


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