Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Somatically generated mutations in the estrogen receptor (ER) have been found at the mRNA/cDNA level in human breast cancer biopsies and in established breast cancer cell lines. Aberrantly spliced ER mRNA causes the appearance of truncated or internally deleted ER protein forms. Studies on the functional activity of the ER variants in expression systems have revealed dominant-positive receptors that are transcriptionally active in the absence of estrogen, and dominant-negative receptors that are themselves transcriptionally inactive but that prevent the action of the normal receptor. The ER variants are believed to confer resistance to endocrine therapy in breast cancer patients. Abnormally spliced forms of ER, similar to those in breast cancer, have been reported in human meningiomas.
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PMID:Mutations in the estrogen receptor gene. 758 11

Although 17 beta-estradiol (E2) replacement therapy has been shown to be effective in treating postmenopausal osteoporosis, the underlying mechanism remains unclear. The presence of low levels of functional endogenous estrogen receptor (ER) in some osteoblastic cells has been demonstrated, and the suggestion that the abundance of ER may be rate-limiting in the action of E2 on these cells has been made. To study the mechanism of ER in regard to E2-mediated effects, we stably transfected a human osteosarcoma cell line, SaOS-2, with an expression vector, pMV-7-ER, containing the human ER gene. We characterized six of the stably transfected clones. One of the stable clones, SaOS-2-ER, expressed extra copies of ER genes integrated into the genome as detected by Southern blot analysis, showed a significantly increased level of ER mRNA by RT-PCR, and contained an increased level of ER cytosolic protein as detected by an ER-specific EIA. The overexpressed ER was functional and sensitive to E2 in a dose-dependent fashion after transient transfection with a vector containing an estrogen response element (ERE) linked to a chloramphenicol acetyltransferase (CAT) reporter gene. Scatchard analysis revealed a single high-affinity binding site with a Kd similar to values obtained for the ER in MCF-7 breast cancer cells. These SaOS-2-ER cells had altered osteoblast phenotypic features including growth inhibition, decreased basal alkaline phosphatase activity, and decreased IL-6 expression and secretion. In response to E2, a greater than 2-fold increase in TGF-beta 1 mRNA was quantitatively measured in these ER-overexpressing osteoblasts. These cells may provide a sensitive and unique model for understanding the mechanism of E2 and ER in overall bone metabolism.
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PMID:Generation and characterization of a human osteosarcoma cell line stably transfected with the human estrogen receptor gene. 763 12

1,25(OH)2-Vitamin D3 inhibits breast cancer cell proliferation through interaction with the vitamin D receptor (VDR). Regulation of VDR is under the influence of several factors which include the functional ligand for this receptor (1,25(OH)2-vitamin D3) as well as heterologous steroid hormones. We evaluated the nature of homologous regulation in T-47D human breast cancer cells with a radiolabelled ligand binding assay and a ribonuclease protection assay for VDR. Significant VDR up-regulation, as measured by hormone binding assays, occurred with pre-incubations with 10(-9)M through 10(-6)M 1,25(OH)2-vitamin D3 (P < 0.05). A 7-fold VDR up-regulation with 10(-8)M 1,25(OH)2-vitamin D3 occurred at 4 h treatment and was not associated with an increase in VDR mRNA expression on ribonuclease protection assay. This supports the hypothesis that up-regulation of VDR is probably the result of ligand-induced stabilization of pre-existing receptor. All-trans-retinoic acid, the progesterone analog R-5020, and prednisone were found to induce heterologous up-regulation of the VDR. We then determined with ligand binding assays whether 1,25(OH)2-vitamin D3 could influence receptor levels for another hormone in a manner analogous to the heterologous regulation of VDR. Regulation of estrogen receptor (ER) by 1,25(OH)2-vitamin D3 was studied in T-47D and MDA-MB-231 breast cancer cells. Incubation of T-47D cells, which are ER (+), with 10(-8)M 1,25(OH)2-vitamin D3 did not result in up-regulation of ER. Yet estrogen binding was significantly up-regulated in a cell line that is ER(-), MDA-MB-231. The increased estrogen binding was associated with a shift in binding affinity and ribonuclease protection assay showed absence of ER mRNA in these cells, suggesting an up-regulation of estrogen binding proteins and not of the ER itself.
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PMID:Modulation of vitamin D receptor and estrogen receptor by 1,25(OH)2-vitamin D3 in T-47D human breast cancer cells. 766 88

Breast cancer patients with an estrogen receptor (ER) positive tumor can be treated with the anti-estrogen tamoxifen, but development of anti-estrogen resistance is a serious problem. We have analyzed a tamoxifen resistant human breast cancer cell line MCF-7/TAMR-1 for alterations in ER which might explain the tamoxifen resistance. The MCF-7/TAMR-1 cells expressed both wild-type ER mRNA and protein, and by RT-PCR we were able to clone ER cDNAs corresponding to the following mRNA splice variants: ER delta E2, ER delta E4, ER delta E5, ER delta E7 and a new double splice variant lacking both exon 4 and 7 (ER delta E4,7) The existence of the ER delta E4,7 variant was confirmed by RNase protection assay. Semi-quantitative RT-PCR revealed that ER delta E2 mRNA was expressed at a higher level in MCF-7/TAMR-1 cells, whereas the ER delta E5 mRNA was expressed at a significantly lower level in MCF-7/TAMR-1 cells compared with MCF-7 cells. The differential expression of the two ER mRNA splice variants indicates that they may be involved in anti-estrogen resistance, although the present knowledge of their biological function does not provide us with an explanation.
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PMID:Differential expression of estrogen receptor mRNA splice variants in the tamoxifen resistant human breast cancer cell line, MCF-7/TAMR-1 compared to the parental MCF-7 cell line. 766 83

Melatonin, the hormonal product of the pineal gland, has been shown to inhibit the development of mammary tumors in vivo and the proliferation of MCF-7 human breast cancer cells in vitro by mechanisms not yet identified. However, previous studies have demonstrated that melatonin significantly decreased estrogen-binding activity and the expression of immunoreactive estrogen receptor (ER) in MCF-7 breast cancer cells. To determine the mechanism(s) by which melatonin regulates ER expression in MCF-7 cells, the relationship between the level of steady state ER mRNA and the rate of ER gene transcription were examined in response to melatonin. Physiological concentrations of melatonin decreased steady state levels of ER mRNA expression in a dose- and time-specific manner. This decrease was not dependent upon the presence of estrogen since similar decreases in steady state ER mRNA levels were seen in MCF-7 cells cultured in both complete and estrogen-depleted media. The decreased expression of ER mRNA in response to melatonin appears to be directly related to the suppression of transcription of the ER gene. This regulation is independent of the synthesis of new proteins, as cycloheximide was unable to block the melatonin-induced decrease of steady-state ER mRNA levels. The down-regulation of ER by melatonin appears to not be mediated via a direct interaction with the ER and subsequent feedback on its own expression, since melatonin treatment did not alter the transcriptional regulatory ability of the fully activated wild type ER or a constitutively active hormone-binding domain-deleted ER variant. In addition, the stability of the ER transcript was unaffected by melatonin. Thus, it appears that the antiproliferative actions of this pineal indoleamine are mediated, at least in part, through the suppression of the transcription of the ER gene in MCF-7 human breast cancer cells.
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PMID:Modulation of estrogen receptor mRNA expression by melatonin in MCF-7 human breast cancer cells. 770 56

The exon 5 deletion splice variant of estrogen receptor (delta 5 ER), which in vitro is constitutively active in the absence of estrogens, may have a role in conferring both tamoxifen resistance and ER-related phenotype in breast cancer. We have investigated the expression of this variant in vivo (at the level of mRNA) in relation to known tamoxifen resistance and expression of the estrogen-regulated genes progesterone receptor (PgR) and pS2. The amount of delta 5 ER mRNA relative to wild type (WT) ER mRNA (% delta 5/WT) was assayed in 70 tamoxifen-resistant and 50 primary breast carcinomas using reverse transcription/PCR. Both WT and delta 5 ER mRNA were detected in the majority of tumors, although delta 5 ER was detected only in the presence of WT ER. Overall no significant difference was seen in % delta 5/WT ER between tamoxifen-resistant and primary control tumors (medians, 13 and 15%, respectively). Tumors in both control and resistant groups which expressed PgR/pS2 in the absence of measurable ER protein (ER- PgR+ and ER- pS2+) had significantly higher delta 5 ER mRNA levels compared with other phenotypes (P < 0.002). This association with ER-/pS2+ tumors has not been demonstrated previously. In ER+ tumors which expressed pS2, significantly greater delta 5 ER mRNA expression was observed in tamoxifen-resistant compared with control tumors (P = 0.05). A similar although nonsignificant trend was observed in ER+ PgR+ tumors. While delta 5 ER mRNA is unlikely to be responsible for tamoxifen resistance in most breast cancers, elevated delta 5 ER mRNA levels may be important in some tumors, especially those which continue to express high levels of PgR/pS2.
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PMID:Exon 5 deletion variant estrogen receptor messenger RNA expression in relation to tamoxifen resistance and progesterone receptor/pS2 status in human breast cancer. 781 59

Using reverse transcription (RT)/PCR we have shown that four breast cancer cell lines expressed oestrogen receptor (ER) mRNA, irrespective of whether they were assessed as ER-positive (MCF-7 and BT-474) or ER-negative (MDA-MB-231 and BT-20) by enzyme immunoassay (EIA). In addition to the wild type (WT) form, they were all found to express the exon 5-deleted variant (V) form of ER mRNA by RT/PCR; this is thought to code for a truncated constitutively active protein. By Northern blot analysis only the ER-positive cell lines (MCF-7 and BT-474) were found to express detectable levels of ER mRNA. Oestradiol-induced growth was found only in the ER-positive (by EIA) cell lines. These results confirm that the differences between ER-positive and ER-negative cell lines are quantitative rather than qualitative. As low levels of ER mRNA could be detected by RT/PCR, this may reflect the greater sensitivity of this approach. The presence of exon 5-deleted V form ER mRNA in addition to the WT form in all four breast cancer cell lines may allow these lines to be used to assess differential regulation of transcription and the impact of this on their oestrogen dependence.
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PMID:Detection of wild type and exon 5-deleted splice variant oestrogen receptor (ER) mRNA in ER-positive and -negative breast cancer cell lines by reverse transcription/polymerase chain reaction. 789 44

All-trans retinoic acid (tRA) inhibits growth of estrogen receptor-positive (ER+) breast cancer cells in vitro, and a variety of retinoids inhibit development of breast cancer in animal models. 9-cis retinoic acid (9-cis RA) is a naturally occurring high affinity ligand for the retinoid X receptors, as well as the retinoic acid receptors (RARs). Whether 9-cis RA has a different spectrum of biological activity from tRA, which only binds RARs with high affinity, is largely unknown. We studied the effects of 9-cis RA on growth and gene expression in ER+ and ER- human breast cancer cells. 9-cis RA inhibited the growth in monolayer culture of several ER+, but not ER-, cell lines in a dose-dependent manner. Growth inhibition and morphological changes by 9-cis RA were similar to those of tRA, suggesting that the ability to bind both RAR and retinoid X receptors did not significantly augment growth inhibition or confer sensitivity to tRA-resistant lines. MCF-7 cells exposed to 9-cis RA showed a dose-dependent accumulation in G1. Northern analyses showed that RAR-alpha and RAR-beta were not significantly regulated, while RAR-gamma was up-regulated and retinoid X receptor alpha was down-regulated by 9-cis RA. Since interactions between tRA and ER-dependent transcription have recently been reported, we investigated whether these retinoids regulate expression of ER itself or estrogen-responsive genes. Both 9-cis RA and tRA induce down-regulation of ER mRNA and protein in MCF-7 cells. 9-cis RA down-regulates expression of the estrogen-responsive genes PR and pS2 in MCF-7 cells as reported previously for tRA. In several ER-positive subclones, we found that the degree of ER expression and regulation, but not always estrogen-sensitivity, correlates with the growth-inhibitory effects of 9-cis RA. Further, in an ER-, retinoid-unresponsive breast cancer cell line, induced ER expression confers responsiveness to retinoid growth inhibition. These data, combined with reports of additive growth inhibition of tRA and tamoxifen in vitro, suggest that 9-cis RA might augment the ability of tamoxifen to inhibit growth of ER+ breast cancer cells in vivo.
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PMID:9-Cis retinoic acid inhibits growth of breast cancer cells and down-regulates estrogen receptor RNA and protein. 798 55

The imbalance between proliferative and differentiative estrogenic effect, caused by quantitative and qualitative alteration of the estrogen receptor (ER) expression, may play a determinant role in mammary neoplastic transformation. Our studies demonstrate that ER levels are significantly higher in human mammary neoplastic tissues when compared to perineoplastic tissues and that increased ER expression is associated with ER gene hypomethylation. During progressive multifactorial carcinogenesis, ER overexpression may represent an early step in neoplastic transformation. In fact, high levels of ER represent good markers of differentiation and can predict the likelihood of benefiting from anti-estrogen therapy. Nevertheless, about 35% of ER-positive breast cancers are resistant to endocrine therapy and 10% of ER-negative tumors behave as hormone-sensitive tumors. Recent studies on ER mRNA variants, which naturally occur in human breast tumors, demonstrated mutations, deletions and alternative splicings, yielding deletions of exons 3, 4, 5 and 7. ER variants exhibited altered functions or changed the responsiveness to hormonal therapy. Analysis of these variants could be a useful parameter to better predict tumor responsiveness to anti-estrogen therapy. Recently, a regain of hormonal responsiveness by ER-negative breast cancer cells has been reported following ER gene transfection. However, estradiol treatment inhibits rather than stimulates cell growth as well as the metastatic and invasive potential of the ER gene transduced cells. Transfer of the ER gene may be considered as a new therapeutic approach in the management of hormone-independent breast cancer.
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PMID:Estrogen receptors: new perspectives in breast cancer management. 804 96

Both retinoic acid (RA) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elicit a number of common biochemical and toxic responses including teratogenic effects in mice and inhibition of cell proliferation of numerous cell lines. In mice, RA plus TCDD interact synergistically as teratogens, suggesting a link between the RA and aryl hydrocarbon receptor signal transduction pathways. In this study, it was shown that both RA and TCDD elicit a number of common responses in MCF-7 human breast cancer cells, including inhibition of estrogen-induced cell proliferation and [3H]thymidine uptake, inhibition of nuclear estrogen receptor (ER) ligand binding, and interactions with a consensus [32]estrogen-responsive element in a gel mobility shift assay. RA and TCDD also decrease steady-state ER mRNA levels in a time-dependent manner. Moreover, interactive studies in which cells were treated with both RA plus TCDD also resulted in decreased responses.
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PMID:Interaction of 2,3,7,8-tetrachlorodibenzo-p-dioxin and retinoic acid in MCF-7 human breast cancer cells. 804 42


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