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

This article summarizes recent research on the development of estrogen receptor alpha (ER alpha) and estrogen receptor beta (ER beta) subtype-selective ligands based on our understanding of structure-activity relationships in these two estrogen receptors and differences in their ligand binding domains and activation function domains. The use of these ligands should enable greater understanding of the unique biologies mediated by ER alpha versus ER beta and may, as well, provide selective estrogen receptor modulators having unique biological and pharmacological profiles optimal for prevention and treatment of breast cancer, for menopausal hormone replacement, for prevention of osteoporosis, and for potential cardiovascular benefit.
 ...
PMID:Structure-function relationships in estrogen receptors and the characterization of novel selective estrogen receptor modulators with unique pharmacological profiles. 1179 81

We determined the differential response of a novel SERM, SP500263, on estrogen receptor (ER) alpha and the more recently cloned ER-beta. Because of the high homology of amino acid residues in the ligand-binding domain of ER-alpha and ER-beta, we were not surprised to find that SP500263 binds to both ERs equally well. In contrast, SP500263 acts as a strong estrogen agonist in a strictly ER-alpha-specific manner in U2OS osteosarcoma cell lines blocking the production of interleukin (IL) 6 and granulocyte macrophage colony-stimulating factor. SP500263 also blocked IL-6 production in primary bone cells. The mechanism of this inhibition is different from the classic estrogen stimulation involving an estrogen response element (ERE). SP500263 does not activate gene expression through an ERE. In contrast to the results observed in U2OS cells, SP500263 acts as a strong estrogen antagonist in an MCF-7 breast cancer proliferation assay. Therefore, SP500263 is a member of a series of next-generation SERMs with functional selectivity toward ER-alpha and a mixed agonist/antagonist profile in a bone cell assay versus a breast cancer assay. The panel of assays described herein allow for the development of receptor-specific ligands that may be further developed into novel pharmaceuticals with an improved profile for the treatments of osteoporosis and breast cancer.
 ...
PMID:Differential response of estrogen receptors alpha and beta to SP500263, a novel potent selective estrogen receptor modulator. 1185 36

Women are exposed to xenobiotic estrogens at least to the same extent as men. These estrogenic chemicals are either from plant material in the diet (phytoestrogens) or from industrial sources. Mainly industrially derived environmental estrogens may accumulate within the food chain and persist in human adipose tissue. In contrast, phytoestrogens do not bioaccumulate and are rapidly excreted in urine. The phytoestrogens probably represent the source of most extensive exposure for humans. Epidemiological evidence suggests that diets rich in phytoestrogens are associated with reduced incidences of cardiovascular disease, breast cancer, prostate cancer and osteoporosis. The numerous bioactivities (other than just estrogenicity) of phytoestrogens and related dietary compounds make it difficult to single out the mechanisms mediating such protective effects. The possibility that the newly discovered estrogen receptor beta may be an important modulator of phytoestrogen action is opening up new lines of research. While the evidence suggests that phytoestrogens may be of positive relevance to postmenopausal women, indications that exposure of women to industrially derived xenobiotic estrogens provides risks to health remain unproven. Further work is necessary to clarify the relative importance of 'xenobiotic' estrogens to human health, but it must be emphasized that the estrogenic potency of all the xenobiotic estrogens is very low compared with that of endogenous estrogens.
 ...
PMID:How significant are environmental estrogens to women? 1190 47

Four different human tissues and breast cancer cell lines were screened to identify exon deletion variant transcripts of estrogen receptor beta (ERbeta) by reverse transcription-polymerase chain reaction using the 'splice targeted primer approach' that amplifies each category of exon deleted variants as a separate gene population. A total of 10 different variant mRNAs that have deletions in various combination of exons were identified by sequence analysis. They were exon 2Delta; exons 2 and 5-6Delta; exon 3Delta; exon 4Delta; exon 5Delta; exons 5 and 2Delta; exon 6Delta; exons 6 and 2Delta; exons 6, 2-3Delta; and exons 5-6Delta. In some cases, deletion of an exon appears to be associated with a mutation of a specific base. Although ERalpha and ERbeta are highly homologous, have identical exon and functional domain organization, exhibit similar ligand-binding profiles and interact with identical DNA response elements, the sequence of exon skipping in ERbeta pre-mRNA appears to be distinct from that of ERalpha mRNA. Furthermore, results described here also suggest that alternate splicing of ERbeta mRNA is tissue specific. The presence of a ERbeta variant profile together with other ER isoforms in a tissue may have functional implications in binding and response to a particular ligand.
 ...
PMID:Identification of ten exon deleted ERbeta mRNAs in human ovary, breast, uterus and bone tissues: alternate splicing pattern of estrogen receptor beta mRNA is distinct from that of estrogen receptor alpha. 1195 19

Estrogen receptor alpha (ER-alpha) is an important regulator of growth and differentiation in the mammary gland and the female reproductive tract. It is also involved in the development of malignant tumors. The human ER-beta is highly homologous to the extensively studied human ER-alpha. It binds to the endogenous 17beta-estradiol with similar affinity as ER-alpha and the transcriptional activity through the consensus ERE can be stimulated. Five ER-beta isoforms were cloned and characterized. They diverge at a common position within the predicted helix 10 of the ligand-binding domain of the human ER-beta, with nucleotide sequences consistent with different exon usage. These isoforms of human ER-beta show differential expression in tissues and in tumor cell lines. Furthermore, they are predicted to form DNA-binding heterodimers when coexpressed. Expression of some of the ER-beta isoforms in human breast tissue, breast cancer, and breast cancer cell lines were reported by several groups. However, there is no complete analysis of the gene expression pattern of all ER-beta isoforms in breast cancer so far. In this study, we examined the mRNA expression of each of the ER-beta isoforms in 30 tumors from breast cancer patients and 21 breast cell lines. In conclusion, expression of ER-beta1, ER-beta2, and ER-beta5 were observed in different cell lines as well as in the tumors, ER-beta4 isoform was expressed in all samples, and ER-beta3 isoform was not detected in any of the samples examined. There were no associations of the expression of all ER-beta isoforms with the invasiveness of the cell lines as well as with clinical parameters of the tumors.
Breast Cancer Res Treat 2002 Feb
PMID:Expression of estrogen receptor beta isoforms in human breast cancer tissues and cell lines. 1200 43

When estrogen binds its receptor (ER), it becomes a potent mitogen in a number of target tissues including the mammary gland where it plays an important role in the pathogenesis of mammary carcinoma. Arsenic trioxide (AS2O3), a clinically effective agent against acute promyelocytic leukemia, has been shown to induce apoptosis in a variety of cancer cells in vitro. Here, we investigated the effects of AS2O3 on the growth of two ER-positive breast cancer cell lines, MCF7 and T47D in vitro. We found that higher doses of AS2O3 dramatically reduced the survival of these two breast cancer cell lines while lower doses of AS2O3 significantly inhibited the expression of estrogen receptor alpha (ER-alpha), but did not effect ER-beta expression. The ER-alpha expression is totally restored when AS2O3 is absent for 24 hours. Using a reporter gene controlled by ER, we further demonstrated that AS2O3 strongly-repressed 17beta-estradiol (E2) stimulated-transcriptional activation. Moreover, AS2O3 abolished transcriptional induction of the estrogen responsive gene pS2 mediated by E2. These results indicated that AS2O3 specifically inhibits expression and signaling pathway of the ER-alpha. We suggest that AS2O3 in combination with other methods might provide a novel therapeutic approach for ER-alpha-positive breast cancer.
 ...
PMID:Functional repression of estrogen receptor a by arsenic trioxide in human breast cancer cells. 1201 31

Two oestrogen receptors (ERs), ER alpha and ER beta, have been identified. ER alpha is by far the better characterized and is an established predictive marker in breast cancer which influences decisions on whether or not to give adjuvant anti-oestrogens, such as tamoxifen. In contrast, the function of ER beta in breast pathobiology is unclear, partly because most studies have focused on its mRNA rather than the protein. In this review, the significance of ER beta in the human breast is reviewed with respect to recent literature and its possible implications are discussed.
 ...
PMID:Oestrogen receptor beta in breast cancer: good, bad or still too early to tell? 1201 36

Selective estrogen receptor modulator is a proven agent for chemoprevention and chemotherapy of cancer. Raloxifene, a mixed estrogen agonist/antagonist, was developed to prevent osteoporosis and potentially reduce the risk of breast cancer. In this study, we examined the effect of raloxifene on the TSU-PR1 cell line. This cell line was originally reported to be a prostate cancer cell line, but recently it has been shown to be a human bladder transitional cell carcinoma cell line. The TSU-PR1 cell line contains high levels of estrogen receptor beta. Following treatment with raloxifene, evidence of apoptosis, including change in nuclear morphology, DNA fragmentation, and cytochrome c release, was observed in a dose-dependent manner in the TSU-PR1 cells (10(-9) to 10(-6) m range). We observed no detectable change in the steady-state levels of Bax, Bcl-2, and Bcl-X(L) following raloxifene treatment. However, raloxifene induced caspase-dependent cleavage of BAD to generate a 15-kDa truncated protein. Overexpression of a double mutant BAD resistant to caspase 3 cleavage blocked raloxifene-induced apoptosis. These results demonstrate that raloxifene induces apoptosis through the cleavage of BAD in TSU-PR1 cells. This molecular mechanism of apoptosis suggests that raloxifene may be a therapeutic agent for human bladder cancer.
 ...
PMID:Raloxifene, a mixed estrogen agonist/antagonist, induces apoptosis through cleavage of BAD in TSU-PR1 human cancer cells. 1208 14

Raloxifene, a selective estrogen receptor (ER) modulator, is a mixed estrogen agonist/antagonist that has been shown to prevent osteoporosis and breast cancer in women. Because the prostate contains a high level of ER-beta, the present study investigated the effect of raloxifene in the androgen-sensitive human prostate cancer cell line LNCaP. Previously, it has been demonstrated that LNCaP cells express ER-beta but not ER-alpha and that tamoxifene induces apoptosis in these cells. After treatment with raloxifene, a dramatic increase in cell death occurred in a dose-dependent manner (10(-9) to 10(-6) M range). Using the terminal deoxynucleotidyl transferase-mediated nick end labeling apoptotic assay, we demonstrated that the nuclear fragmentation was due to apoptosis. The dramatic change in cellular morphology after treatment with raloxifene was no longer observed when cells were pretreated with a pan-caspase inhibitor, Z-VAD-FMK, and a specific caspase-9 inhibitor, Z-LEHD-FMK. Furthermore, immunoblot demonstrated an activation of caspase-9 in LNCaP cells. Because LNCaP cells contain a mutated androgen receptor that allows cellular proliferation in the presence of antiandrogens, prostate-specific antigen assay and transfection with a reporter construct containing luciferase gene under the control of androgen response element (pARE) were carried out. The results demonstrated that raloxifene does not significantly alter androgen receptor activity in LNCaP cells. Taken together, these results demonstrate that raloxifene, a selective ER modulator, induces apoptosis in the androgen-sensitive human prostate cancer cell line LNCaP through an androgen-independent pathway.
 ...
PMID:Raloxifene, a selective estrogen receptor modulator, induces apoptosis in androgen-responsive human prostate cancer cell line LNCaP through an androgen-independent pathway. 1209 69

Hormone receptor content is the most useful parameter for predicting hormone response therapy in breast cancer. The high frequency of primary and secondary resistance to treatment makes it necessary to find out other parameters in order to improve the prediction of response to treatment. The newly described estrogen receptor beta (ERbeta) is a potential candidate. Using real-time quantitative RT-PCR, we evaluated estrogen receptor alpha (ERalpha), ERbeta, and progesterone receptors (PR) in comparison with ERalpha and PR protein content measured with the enzyme immunoassay (EIA), in a retrospective series of 98 breast tumors. We obtained a highly significant correlation between mRNA and EIA assays for ERalpha and PR (r=0.79 and r=0.71, respectively; P<0.001). We confirmed the low level of ERbeta mRNA transcripts in comparison to ERalpha in breast tumors. We did not find any statistically significant correlation between the absolute ERbeta mRNA level and ERalpha or PR mRNA level, and ERalpha or PR-EIA. We found a significant correlation between ERalpha mRNA and PR mRNA expressions. We did not find any correlation between ERbeta mRNA and clinical features of the patients (age, menopausal status, tumor size, and nodal status), nor with the histological type of the tumor. In conclusion, the accuracy of the present quantitative RT-PCR assay makes it suitable for a routine clinical use. In addition, the present results suggest that, ERbeta mRNA expression is independent of the classical parameters.
 ...
PMID:Quantitation of estradiol receptors alpha and beta and progesterone receptors in human breast tumors by real-time reverse transcription-polymerase chain reaction. Correlation with protein assays. 1214 3


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>