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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this work was to determine the extent of estrogen receptor beta (ER-beta) expression in invasive breast cancer (BrCA) and whether ER-beta expression is correlated with response to adjuvant hormonal therapy with tamoxifen (AHTT). Immunohistochemical staining (IHC) for estrogen receptor alpha (ER-alpha) and ER-beta was performed on sections of formalin-fixed and paraffin-embedded tissue from 47 unselected invasive breast carcinomas (BrCA). IHC for ER-beta was also performed on sections of BrCA from 118 women who were treated with mastectomy and AHTT. Survival analysis was performed using the Kaplan-Meier method and the log-rank test. Of the 47 unselected BrCA, 17 (36%) were negative for ER-alpha and of these, 8 (47% of ER-alpha negative cases and 17% of all 47 patients) were ER-beta positive. Five of the 8 ER-alpha negative and ER-beta positive cases were positive for ER biochemically. There was no correlation between ER-beta positivity and overall survival in the unselected group. By contrast, in the group of women treated with AHTT, expression of ER-beta in more than 10% of cancer cells was associated with better survival (P = .0077), even in women with node-negative BrCA (P = .0069). In conclusion, our results show that a significant number of women with BrCA are positive for ER-beta only, and may be determined to be ER-negative when currently available IHC is used. ER-beta status is a significant predictor of response to AHTT in women with BrCA. Larger studies with multivariate analysis are needed to confirm these findings.
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PMID:Estrogen receptor beta expression in invasive breast cancer. 1117 4

Overexpression of the oncoprotein MDM2, a negative feedback regulator of p53, is often observed in breast cancer tissue and cell lines, particularly in those which express estrogen receptor alpha (ERalpha). In this study, we report a novel function of MDM2, i.e., as a positive regulator of ERalpha. This function does not involve p53. MDM2 overexpressing clones derived from the breast cancer cell line, MCF-7 cells, showed a remarkable growth advantage only in estradiol supplemented conditions, and this profile coincided with increased transcriptional activity of ERalpha in these cells. Though p53 has been reported to be an inhibitor of ERalpha function, p53 protein in MDM2 overexpressing clones was more abundant than in the parental cells. When ERalpha was exogenously expressed in p53-null cells, its activity was enhanced by coexpression of MDM2. Mammalian two-hybrid assays and GST pull-down assays indicated that MDM2 could interact with ERalpha. These results indicate that MDM2 is a direct activator of ERalpha function, and suggest such a role for MDM2 in ERalpha-positive breast cancer.
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PMID:MDM2 enhances the function of estrogen receptor alpha in human breast cancer cells. 1117 89

Treatment of MCF-7 human breast cancer cells with 17beta-estradiol (E(2)) results in increased DNA synthesis and cell proliferation and enhanced enzyme activities associated with purine/pyrimidine biosynthesis. The mechanism of enhanced DNA polymerase alpha activity was investigated by analysis of the promoter region of this gene. E(2) induced luciferase (reporter gene) activity in MCF-7 cells transfected with pDNAP1, pDNAP2, and pDNAP3 containing -1515 to +45, -248 to +45 and -116 to +45 inserts from the DNA polymerase alpha gene promoter, whereas no induction was observed with pDNAP4 (-65 to +45 insert). The induction response was dependent on cotransfection with estrogen receptor alpha (ER(alpha)), and transactivation was also observed with a mutant ER(alpha) that did not express the DNA-binding domain. Subsequent functional, DNA binding, and DNA footprinting studies showed that a GC-rich region at -106 to -100 was required for E(2)-mediated transactivation, and Sp1 protein, but not ER(alpha), bound this sequence. Transcriptional activation of DNA polymerase alpha by E(2) is associated with ER(alpha)/Sp1 action at a proximal GC-rich promoter sequence, and this gene is among a growing list of E(2)-responsive genes that are induced via ER(alpha)/Sp1 protein interactions that do not require direct binding of the hormone receptor to DNA.
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PMID:Transcriptional activation of deoxyribonucleic acid polymerase alpha gene expression in MCF-7 cells by 17 beta-estradiol. 1118 12

Polyamines are essential for cell growth and differentiation. Structural polyamine analogues have been shown to have antitumor activity in experimental models including breast cancer. The ability of polyamine analogues to alter activity of cytotoxic chemotherapeutic agents in breast cancer models has not been evaluated. This study evaluates the ability of two polyamine analogues, N1-ethyl-N11-[(cyclopropyl)methyl]-4,8-diazaundecane (CPENSpm) and N1-ethyl-N11-[(cycloheptyl)methyl]-4,8-diazaundecane (CHENSpm) to synergize with cytotoxics in five human breast cancer cell lines. Antagonism, additivity, or synergy of the combinations was determined using the median effect/combination index model. The chemotherapeutic agents chosen, cis-diaminechloroplatinum(II), doxorubicin, 5-fluorouracil, fluorodeoxyuridine, 4-hydroperoxycyclophosphamide, paclitaxel, docetaxel, and vinorelbine, all have antitumor activity in breast cancer and represent a spectrum of mechanisms. Three treatment schedules of polyamine analogue and cytotoxic were tested in MCF-7 and MDA-MB-468 lines, demonstrating a schedule-dependence of synergistic growth inhibition. Cytotoxic agent alone for 24 h followed by polyamine analogue alone for 96 h resulted in the most synergistic combinations and the greatest synergy. This schedule was then tested in three additional breast cancer lines, and several synergistic combinations were again identified. Two cytotoxics, vinorelbine and the fluoropyrimidines, showed the most promise in combination with the polyamine analogues. They were able to synergize with one or both polyamine analogues in most of the breast cancer cell lines. CPENSpm was also able to synergize with virtually all of the cytotoxics in the estrogen receptor alpha-positive MCF-7 and T-47D lines. These preclinical data demonstrate a treatment schedule and combinations of polyamine analogues and cytotoxics that will be important to study mechanistically and clinically for breast cancer.
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PMID:Combination of standard cytotoxic agents with polyamine analogues in the treatment of breast cancer cell lines. 1123 95

Estrogen receptors (estrogen receptor alpha, ER) belong to a family of ligand-modulated transcription factors that play an important role in the progression of such tumors as breast and endometrial cancers. Functional domains, a set of mutations and variants produced by internal deletions of ER mRNA, have mainly been identified in breast cancer. Experimental results suggest that the presence of variants may result in different proteins which differ in activity and modulate the ER signaling pathway differently. We analyzed samples from 21 cases of endometrial hyperplasia and from 29 cases of endometrial cancer for the presence of internal exons and exon deletion variants of ER mRNA. ER and progesterone receptor (PgR) proteins were measured using Western blot technique in all endometrial cancer samples. We found that absence of the wild-type exon PCR product of ER mRNA in a sample increased in parallel with malignant potential in both sample types, whereas the number of exon deletion variants detected in the same sample decreased in cases of malignancy. The precise deletions of the respective exons suggest that they are probably the result of splicing errors. A relatively high number of variants in hyperplasia samples may indicate the important role of ER mRNA variants in the physiologic regulation of transcription in estrogen-sensitive genes. Eleven of 29 adenocarcinomas expressed a 62-kDa ER protein, truncated at the amino terminal, whereas all but one sample expressed a short 52 kDa variant ER protein. Our results suggest that differing ER proteins are generally present in human endometrial adenocarcinomas and that they may influence the estradiol signaling pathways.
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PMID:Exon deletions and variants of human estrogen receptor mRNA in endometrial hyperplasia and adenocarcinoma. 1124 Jun 64

Two different isoforms of progesterone receptor (PR), PRA and PRB, are expressed in target tissues at comparable levels. In this study, we first examined PRA and PRB immunoreactivity in human breast cancer and various intraductal proliferative epithelial lesions, and correlated these findings with clinicopathologic parameters. We then examined mRNA expression of PRA and PRB in six cases of invasive ductal carcinoma using RT-PCR. Immunoreactivity for both PRA and PRB was positive in the great majority of proliferative disease without atypia (PDWA) (85% for PRA and 96% for PRB) and atypical ductal hyperplasia (ADH) (100% for PRA and 100% for PRB), but the ratio of immunopositive cases and immunohistochemical (IHC) scores was significantly smaller in ductal carcinoma in situ (DCIS) (65% for PRA and 75% for PRB) and invasive ductal carcinoma (IDC) (66% for PRA and 55% for PRB) than in PDWA and ADH. There was a significant positive correlation between IHC scores for PRA and estrogen receptor alpha (ERalpha) in IDC, DCIS and ADH but not between PRB and ERalpha. In IDC, both PRA and PRB IHC scores were significantly associated with histological grade, but there was no association between PRA or PRB status and lymph node involvement, tumor size, or prognosis of the patients. The expression of mRNAs for both PRA and PRB was detected in all six cases of IDC examined. These results suggest that both PRA and PRB are strongly associated with ERalpha in human breast and this relation may be disturbed in breast cancer.
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PMID:Progesterone receptor A and B isoforms in the human breast and its disorders. 1126 40

Although many series of estrogen receptor antagonists continue to be produced, the majority are direct structural analogues of existing modulators. To examine the tolerance of the estrogen receptor toward flexible ligands, a series of novel flexible estrogen receptor antagonists were prepared and their antiproliferative effects on human MCF-7 breast tumor cells investigated. Each of these compounds deviated from the traditional triphenylethylene backbone associated with common tamoxifen analogues through the introduction of a flexible methylene (benzylic) spacing group between one of the aryl rings and the ethylene group and through variations in the basic side chain moiety. The compounds prepared, when assayed in conjunction with a tamoxifen standard, demonstrated high potency in antiproliferative assays against an MCF-7 human breast cancer cell line with low cytotoxicity and high binding affinity. A computational study was undertaken to investigate the compounds' potential interactions with specific residues within the human estrogen receptor alpha ligand-binding domain (ER-LBD), predicting these compounds bind in an antiestrogenic fashion within the ER-LBD and interact with those important residues previously identified in the structures of ER-LBD agonist/antagonist cocrystals. These compounds further illustrate the eclectic nature of the estrogen receptor in terms of ligand flexibility tolerance.
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PMID:Flexible estrogen receptor modulators: design, synthesis, and antagonistic effects in human MCF-7 breast cancer cells. 1129 54

Human breast tumorigenesis is promoted by the estrogen receptor pathway, and nuclear receptor coactivators are thought to participate in this process. Here we studied whether one of these coactivators, AIB1 (amplified in breast cancer 1), was rate-limiting for hormone-dependent growth of human MCF-7 breast cancer cells. We developed MCF-7 breast cancer cell lines in which the expression of AIB1 can be modulated by regulatable ribozymes directed against AIB1 mRNA. We found that depletion of endogenous AIB1 levels reduced steroid hormone signaling via the estrogen receptor alpha or progesterone receptor beta on transiently transfected reporter templates. Down-regulation of AIB1 levels in MCF-7 cells did not affect estrogen-stimulated cell cycle progression but reduced estrogen-mediated inhibition of apoptosis and cell growth. Finally, upon reduction of endogenous AIB1 expression, estrogen-dependent colony formation in soft agar and tumor growth of MCF-7 cells in nude mice was decreased. From these findings we conclude that, despite the presence of different estrogen receptor coactivators in breast cancer cells, AIB1 exerts a rate-limiting role for hormone-dependent human breast tumor growth.
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PMID:Ribozyme targeting demonstrates that the nuclear receptor coactivator AIB1 is a rate-limiting factor for estrogen-dependent growth of human MCF-7 breast cancer cells. 1132 19

Cyr61, a member of the CCN (CTGF/Cyr61/NOV) family of growth regulators, is a secreted cysteine-rich proangiogenic factor that has been implicated in tumorigenesis. Previous studies have also demonstrated that Cyr61 is regulated by 17beta-estradiol (E(2)) in the uterus. Therefore, we hypothesized that hormonal regulation of Cyr61 may be important in estrogen-dependent pathogenic processes such as breast tumorigenesis. Our study demonstrates that both Cyr61 messenger RNA and protein are induced by E(2) in MCF-7 mammary adenocarcinoma cells that primarily overexpress estrogen receptor alpha (ERalpha) in a dose-dependent and immediate early fashion. Cyr61 gene induction by E(2) is transcriptionally regulated by ERalpha as the antiestrogen, ICI 182,780, and actinomycin D blocked induction completely. In addition, Cyr61 is up-regulated in MCF-7 cells by epidermal growth factor (EGF) in an immediate early fashion as well. The functional relevance of steroid induction of Cyr61 in breast cancer cell growth is demonstrated by anti-Cyr61 neutralizing antibodies, which diminished E(2) and EGF-dependent DNA synthesis and dramatically reduced E(2)-driven cell proliferation by more than 70%. Most importantly, Cyr61 is overexpressed in 70% (28 of 40) of breast cancer patients with infiltrating ductal carcinoma and is localized exclusively to hyperplastic ductal epithelial cells. Moreover, the levels of Cyr61 protein are higher in breast tumors that are ER(+)/EGF receptor(+) than those that are ER(-)/EGF receptor(+), suggesting that estrogens may mediate Cyr61 expression in vivo. Collectively, our data suggest that Cyr61 may play a critical role in estrogen- as well as growth factor-dependent breast tumor growth.
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PMID:Cyr61, a member of the CCN family, is required for MCF-7 cell proliferation: regulation by 17beta-estradiol and overexpression in human breast cancer. 1135 3

Adenosine deaminase (ADA) regulates cellular levels of adenosine and deoxyadenosine, and 17beta-estradiol (E(2)) induces ADA mRNA in MCF-7 human breast cancer cells. IGF-I also induces ADA gene expression in these cells, and induction of this response through IGF activation of estrogen receptor alpha (ERalpha) was further investigated. IGF and other polypeptide growth factors induce reporter gene expression in MCF-7 cells cotransfected with ERalpha expression plasmid and pADA211, a construct containing the -211 to +11 region of the ADA gene promoter which is required for high basal and E(2)-inducible activity. Deletion analysis of this promoter demonstrates that IGF activates ERalpha/Sp1 interactions with multiple GC-rich sites in the promoter and this response is abrogated in cells transfected with ERalpha containing mutations at Ser(118) or Ser(163). IGF induces both MAPK (mitogen-activated protein kinase) and PI3-K (phosphatidylinositol-3-kinase) phosphorylation cascades in MCF-7 cells; however, using a series of inhibitors and dominant negative constructs, our results show that induction of ADA by IGF activation of ERalpha/Sp1 is dependent on the MAPK signaling pathway.
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PMID:Activation of adenosine deaminase in MCF-7 cells through IGF-estrogen receptor alpha crosstalk. 1135 58


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