Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is great concern over the long-term influence of oral contraceptives on the development of breast cancer in women. Oestrogens are known to stimulate the growth of human breast cancer cells, and this laboratory has previously reported (Jeng & Jordan, 1991) that the 19-norprogestin norethindrone could stimulate the proliferation of MCF-7 human breast cancer cells. We studied the influence of the 19-norprogestins norgestrel and gestodene compared to a 'non' 19-norprogestin medroxyprogesterone acetate (MPA) on MCF-7 cell proliferation. The 19-norprogestins stimulated proliferation at a concentration of 10(-8) M, while MPA could not stimulate proliferation at concentrations as great as 3 x 10(-6) M. The stimulatory activity of the 19-norprogestins could be blocked by the antioestrogen ICI 164,384, but not by the antiprogestin RU486. Transfection studies with the reporter plasmids containing an oestrogen response element or progesterone response element (vitERE-CAT, pS2ERE-CAT, and PRE15-CAT) were performed to determine the intracellular action of norgestrel and gestodene. The 19-norprogestins stimulated the vitERE-CAT activity maximally at 10(-6) M, and this stimulation was inhibited by the addition of ICI 164,384. MPA did not stimulate vitERE-CAT activity. A single base pair alteration in the palindromic sequence of vitERE (resulting in the pS2ERE) led to a dramatic decrease in CAT expression by the 19-norprogestins, suggesting that the progestin activity required specific response element base sequencing. PRE15-CAT activity was stimulated by norgestrel, gestodene and MPA at concentrations well below growth stimulatory activity. This stimulation could be blocked by RU486. These studies suggest that the 19-norprogestins norgestrel and gestodene stimulate MCF-7 breast cancer cell growth by activating the oestrogen receptor.
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PMID:Norgestrel and gestodene stimulate breast cancer cell growth through an oestrogen receptor mediated mechanism. 849 28

In this report, we have analyzed the function of two Sp1 sites present in the epithelium-specific MUC1 promoter. Using promoter-reporter gene (CAT) constructs, we found that mutagenesis of either of the Sp1 binding motifs at -576/-568 and -99/-90, reduced transcription in MUC1-expressing epithelial cell lines. However, abolition of the binding site at -99/-91 by mutagenesis also resulted in increased transcriptional activity in non-epithelial cell lines, suggesting involvement of the site in tissue-specific expression. In vitro binding assays revealed a novel binding motif at -101/-89 (AGGGGGCGGGGTT), which overlaps but differs from the Sp1 consensus motif by having an adenine residue in the 5'-flanking sequence. The 5'-flanking sequence appeared to be important for binding of an Sp1-unrelated factor (SpA) but not for binding of Sp1. Site-directed mutagenesis of the motif into a site able to bind Sp1, but unable to bind SpA, resulted in an increased level of transcription of the CAT reporter gene in all cell lines tested, suggesting a repressive effect of the novel factor on transcription. The ratio between the Sp1 and SpA binding activity in nuclear extracts correlated with both promoter activity and the levels of endogenous transcription in different breast cancer cell lines. Our results are consistent with the idea that the relative activities of the two factors may be involved in the up-regulation of expression of the MUC1 gene seen in breast and other carcinomas.
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PMID:Two GC boxes (Sp1 sites) are involved in regulation of the activity of the epithelium-specific MUC1 promoter. 866 95

In addition to their antiprogestational activity, the antiprogestins RU486, ZK98.299 and ZK98.734 possess varying antiglucocorticoid as well as androgen-like or antiandrogen-like properties in human mammary cancer cells. The human mammary cancer cell line MFM-223, which contains only androgen receptors, was used as a model to investigate androgen receptor mediated effects of these antiprogestins. Proliferation of MFM-223 cells is inhibited by androgens and does not respond to oestrogens, progestins and glucocorticoids. As shown in proliferation assays, ZK98.734 was a strong inhibitor of cell proliferation. This effect was antagonised by the antiandrogen hydroxyflutamide. ZK98.734 was found to displace [3H]R1881 from the androgen receptor in MFM-223 cells, substantiating the involvement of the androgen receptor. The antiprogestin ZK98.299 failed to influence the proliferation of MFM-223 cells. ZK98.299 did not bind to the androgen receptor and was devoid of androgenic or antiandrogenic activity. RU486 bound to the androgen receptor. It was a weak inhibitor of MFM-223 cell proliferation, but the inhibition of proliferation by RU486 was not antagonised by hydroxyflutamide. This effect was probably not mediated by the androgen receptor. RU486 had antiandrogenic activity in this cell line, as it antagonised the inhibitory effect of dihydrotestosterone at a 100-molar excess. These results were confirmed by transfection experiments with an MMTV-CAT construct in the same cell line, demonstrating the biological function of the ZK98.734-androgen receptor complex. ZK98.299 and RU486 were not able to induce CAT activity. The different androgenic or antiandrogenic properties of the antiprogestins investigated should be considered when selecting antiprogestational properties of the antiprogestins investigated should be considered when selecting antiprogestational compounds for clinical applications, as a partial androgenic activity may be of benefit in breast cancer but can have undesired side-effects in other diseases.
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PMID:Androgen-like and anti-androgen-like effects of antiprogestins in human mammary cancer cells. 869 75

The high incidence of breast cancer in Western women has been linked to nutritional factors such as high-fat/low-fibre diet, obesity and timing of weight gain. A mechanism is postulated through which the Western diet could act in conjunction with inadequate exercise and excessive weight gain at the time of a major change in hormonal balance. All these factors favour the manifestation of insulin resistance, and the concomitants of hyperinsulinaemia might then synergise with oestrogen in promoting the development of breast cancer. The mechanism is compatible with the 'breast tissue age' model of mammary carcinogenesis. The concomitants of hyperinsulinaemia could also influence the growth of established disease subsequent to its promotion, and it is suggested that the hypothesis be tested by an adjuvant randomised trial of a high-fibre/low-fat diet in patients following primary surgery for early breast cancer. It has been suggested that the development of insulin resistance may link the Western lifestyle not only to an increased risk of hypertension and arteriosclerosis, but also to increased breast cancer risk. Large abdominal fat deposits in women are frequently a marker of the presence of insulin resistance and are generally associated with an increased level of bio-available oestrogen. There is evidence that predominantly abdominal distribution of fat in women may be a marker of increased breast cancer risk from puberty onwards. Abdominal obesity may however be hidden, and it is more reliably demonstrated by imaging techniques such as CAT or MRI scans, than by anthropometric measurements such as increased waist-to-hip ratio.
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PMID:Obesity and breast cancer. 869 16

The erbB-2 receptor plays an important role in the prognosis of breast cancer. Amplification or overexpression of the erbB-2 proto-oncogene has been detected in 30% of breast cancers and is associated with poor patient prognosis. The significance of erbB-3 and erbB-4 in breast cancer is not yet known. The discovery of the growth factor heregulin (HRG) has allowed us to investigate a number of biological events that are regulated by erbB-2, -3, and -4 signal transduction. To determine the role of HRG in breast cancer tumor progression, we have developed an in vitro/in vivo model. We transfected HRG cDNA into the estrogen receptor (ER)-positive breast cancer cell line, MCF-7, and studied these cells as they progressed from a hormone-dependent to -independent phenotype. The biochemical and biological characteristics presented here demonstrate that overexpression of HRG induces morphological changes in MCF-7 cells as well as erbB-2, erbB-3, and erbB-4 autophosphorylation. MCF-7/ heregulin-transfected cells, which express relatively high levels of HRG, developed estrogen independence and resistance to antiestrogens in vitro and in vivo. This is consistent with a more aggressive hormone-independent phenotype. In contrast with control parental/wild-type cells, estradiol-mediated down-regulation of erbB-2 expression is blocked completely in this particular model system. These results indicate that HRG plays a role in the disruption of ER function. When a transient transfection with an ERE-CAT construct was introduced into these HRG-transfected MCF-7 cells, we observed that the ER was transcriptionally inactive. This suggests that ER signaling is altered in HRG-transfected cells. We observed that overexpression of HRG induces a more aggressive, hormone-independent phenotype that is most likely directly related to the constitutive activation of the erbB-2, erbB-3, and erbB-4 receptor signaling cascade. The data presented here suggest a close cross-regulation between the erbB-2/4 receptors and ER and provide new insights into the mechanism by which breast cancer cells acquire a hormone-independent phenotype.
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PMID:Involvement of heregulin-beta2 in the acquisition of the hormone-independent phenotype of breast cancer cells. 876 33

Because the retinoic acid (RA) signaling pathway regulates cell proliferation and differentiation, inactivation of genes integral to the pathway represents a potential mechanism of carcinogenesis. We have studied in human breast cancer cells (T47D, MCF-7, ZR75-1, MDA-MB-231, and BT20) the expression of a subset of retinoid signaling genes that are themselves transcriptionally up-regulated by RA, the cellular retinol binding protein type I (CRBPI) and the RA receptors (RARs) alpha2, beta2, and gamma2. We find that constitutive expression of these genes is low or undetectable, and that expression levels are seldom responsive to 24 h treatment with 1 microM all-trans or 9-cis RA (Northern blot analysis). This is in contrast to breast fibroblasts, which show RA-dependent expression of all four genes under the same conditions. Moreover, normal human breast epithelial cells express CRBPI and RARbeta2 at the mRNA level, suggesting that loss of expression of these genes is tied to malignant transformation. RARbeta2, but not CRBPI, was also expressed in RA-treated MTSV1-7 cells, an immortalized but nontumorigenic luminal epithelial cell line. Lack of CRBPI and RARbeta2 expression in cancer cells was not due to general impairment of RA signaling, as shown by RA activation of a RARE3-tk-CAT reporter in a subclone of MDA-MB-231 cells that did not express either CRBPI or RARbeta2. These results suggest that at least two independent defects in the expression of proteins that function in retinoid signaling may be involved in breast carcinogenesis.
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PMID:Defective expression of cellular retinol binding protein type I and retinoic acid receptors alpha2, beta2, and gamma2 in human breast cancer cells. 880 Nov 68

Polychlorinated biphenyls (PCBs) are one of the most widespread, persistent man-made products in the ecosystem giving rise to serious environmental contamination and potential hazard to health. The PCBs, in common with other compounds such as the dioxins, have been shown to exert some biological actions mediated through the aryl hydrocarbon receptor. Evidence for interaction of PCBs with other nuclear receptors has been sparse. Here we present evidence that 3,4,3',4'-tetrachlorobiphenyl (TCB) (PCB77), a PCB with high toxicity and significant bioaccumulation, can act as an estrogen with actions mediated through the estrogen receptor. Evidence is presented from multiple assay systems including 1) ligand binding to estrogen receptor in a competitive binding assay, 2) ligand ability to induce estrogen receptor binding to DNA, 3) ligand regulation of gene expression from a transfected exogenous (ERE-tk-CAT) or an endogenous (pS2) estrogen-regulated gene, 4) ligand regulation of cell growth in estrogen-dependent human breast cancer cell lines MCF7 and ZR-75-1, and 5) ligand activity in the immature mouse uterine weight bioassay in vivo. These results demonstrate that TCB (PCB77) can be included in the increasing list of environmental pollutants that possess the ability to mimic estrogen action and be termed an environmental estrogen. Since the concentrations of TCB used here (10(-9) M; 292 ng/liter) are not incompatible with levels of PCB/TCB found in human tissues, these results may have physiological relevance. Use of multiple approaches to study estrogenic action demonstrates that one congener can act as both an agonist and antagonist of estrogen action and that the magnitude of these effects can alter according to the molecular environment.
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PMID:3,4,3',4'-Tetrachlorobiphenyl acts as an estrogen in vitro and in vivo. 884 9

Given the important role of the estrogen receptor (ER) in the development and physiology of the breast, it is essential to delineate the mechanisms responsible for its failed expression in some breast tumors. We have cloned and sequenced a portion of the ER upstream regulatory region from the ER-positive MCF-7 and the ER-negative MDA-MB-231 breast cancer cell lines to determine if sequence alterations in this region account for the ER-negative phenotype of some tumors. From this, we identified a number of variations between the sequences, two of which were determined to be associated with a 50% decrease in CAT activity.
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PMID:Identification of sequence alterations in the upstream regulatory region of the estrogen receptor gene in an ER-negative breast cancer cell line. 906 12

Redox regulation of transcription factors has recently been demonstrated for AP-1, NF-kappaB, Sp-1 and glucocorticoid receptor in vitro and in vivo. The redox state in estrogen-dependent cells possibly influences the function of estrogen receptor (ER), and the regulation of the function of ER is essential for understanding of growth and differentiation of these cells, as well as promotion and progression of estrogen-associated cancer. In this paper, we first analyzed the effects of redox state on transcriptional activity of ER in terms of pS2 mRNA expression and transfection of ERE-CAT plasmid in human breast cancer cells. Addition of H2O2 at low concentrations lowered levels of pS2 mRNA and also down-regulated ERE-CAT activity, which was recovered by transfection of thioredoxin (TRX) expression vector. Next, the transfection of antisense TRX plasmid diminished ERE-CAT activity, and the activity was recovered by co-transfected sense TRX. Furthermore, specific DNA binding activity of recombinant ER was inhibited by sulfhydryl-modifying reagents and restored by the addition of recombinant TRX protein in electrophoretic mobility shift assay. These results in vitro and in vivo revealed that the transcription activity of ER is strongly influenced by its redox state, which is reversibly modulated by endogenous redox effector protein, TRX.
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PMID:Functional modulation of estrogen receptor by redox state with reference to thioredoxin as a mediator. 932 54

The matrix-degrading enzyme family of matrix-metalloproteinases (MMPs) has been implicated in the process of tumour metastasis. Cellular protein and RNA localisation techniques have been used to show that, whilst several MMP genes are expressed in both cancer and stromal cells, stromelysin 3 is expressed only in stromal fibroblasts adjacent to cancer cells. Immunohistochemical and in situ hybridisation evidence suggests that neoplastic cells can stimulate stromal cell MMP production either in a paracrine fashion or by a cell-cell contact mechanism. Using 2 different lengths of the human stromelysin 3 (ST3) gene 5' flanking sequence cloned upstream of luciferase and CAT reporter genes, we now show that human breast cancer cells can directly activate the ST3 promoter. The putative response element in the ST3 promoter, which lies between 0.46 and 3.4 kb upstream of the transcription start site, is able to effect a 2- to 3-fold increase in downstream gene expression. We further show that this transcriptional up-regulation definitely occurs via a paracrine, and possibly via a cell-cell contact, mechanism. Confirmation that this ST3 promoter activation results in ST3 gene induction of a similar magnitude was shown using Northern blotting of stimulated fibroblasts. Our data provide further evidence that cancer cells can induce fibroblast MMP expression and help to explain the in vivo expression pattern of ST3 in breast cancer.
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PMID:Modulation of human stromelysin 3 promoter activity and gene expression by human breast cancer cells. 933 57


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