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

This review of the mechanism of action of the anti-progestational agent RU-486 concentrates on its interactions with the sub-molecular regions of the progesterone receptor, and implications for clinical applications. The progesterone receptor, like other steroid hormone receptors, has 4 distinct regions, the ligand-binding domain (LBD), the DNA-binding domain (DBD), a highly charged hinge region, and an N-terminal section thought to be involved in regulation of transactivation. The progesterone receptor occurs in 2 forms, A and B, and these are linked in dimers. The dimer binds to DNA at locations called hormone response elements (HREs). The receptor remains in the nucleus, prevented from binding by heat shock protein 90 (hsp90). DNA binding, which can occur separately from hormone in experimental conditions, first causes release of hsp90, and a shape change in the receptor, and then elicits an effect on the DNA chromatin, modification of transcription factors, and other effects such as phosphorylation or related proteins. When RU-486 is substituted for progesterone, DNA binding is tight, but the hsp-90-receptor complex is stabilized, and the receptor shape is abnormal, incompatible with subsequent hormone effects in the cell. The implications for research on the mechanism of action of the progesterone receptor were discussed. Examples include the suggestion that the 1% of women who do not respond to RU-486 with early abortion may be genetically distinct; that research of progesterone receptors in several types of cancer such an meningiomas and breast cancer are justified; and alto that use of RU-486 for local or systemic hypercorticism may be applicable. On the other hand, while new users of RU-486 for contraception are theoretically of interest, it is unlikely that any company will invest in another type of oral contraceptive.
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PMID:The steroid hormone antagonist RU486. Mechanism at the cellular level and clinical applications. 177 81

Human progesterone receptors (PR) were overexpressed in Spodoptera frugiperda (Sf9) insect cells using a recombinant baculovirus system. Recombinant viruses were constructed that produced either full-length A (94K) or B (120K) forms of human PR, and each was expressed as a functional protein. Steroid and DNA binding activities were found to be indistinguishable from that of endogenous human PR in T47D breast cancer cells. Moreover, as analyzed by gel-mobility shift, recombinant PR-A and PR-B each bound to specific progesterone response elements in a strictly hormone-dependent manner. Native receptors expressed in Sf9 cells also exhibited structural properties similar to that of endogenous PR. Cytosolic PR (PR-A or PR-B), prepared in low salt buffer, sedimented on density gradients as an 8S oligomeric complex that was converted largely to 4S by treatment with 0.4 M NaCl. Immune isolation of the 8S cytosol PR complex and analysis of protein composition revealed the presence of two specific copurifying proteins of approximately 90K and 70K. The 90-K component was identified immunologically as heat shock protein 90. The 70-K component was not identified but is likely to be the insect equivalent of heat shock protein 70. Immune isolation of PR from Sf9 cells metabolically labeled with [32Pi], revealed that expressed PR was capable of being phosphorylated in insect cells. Hormone addition to Sf9 cells, however, did not stimulate the same increase in PR phosphorylation or upshift in mobility on sodium dodecyl sulfate gels that occurs with endogenous receptors in T47D cells. Thus some, but not all, phosphorylations occur with human PR expressed in Sf9 cells. These phosphorylation data, together with the fact that expressed PR required hormone for DNA binding, indicate that the hormone-dependent phosphorylation step responsible for PR upshifts on sodium dodecyl sulfate-polyacrylamide gel electrophoresis is not required for receptor binding to DNA. The baculovirus expression system, therefore, may prove valuable in dissecting the functional role(s) for both hormone-dependent and hormone-independent PR phosphorylation.
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PMID:Characterization and functional properties of the A and B forms of human progesterone receptors synthesized in a baculovirus system. 177 77

Human meningiomas are rich in progesterone receptors (PR), which appear to be expressed autonomously. To investigate whether estrogen receptor (ER) variants which do not bind the ligand, but may constitutively induce PR expression, prevail in meningioma, we amplified cDNA by PCR in order to detect mRNA coding for the ER in meningioma which were ER-negative/PR-positive at the protein level. We screened for a portion of the ER which includes the DNA binding domain, the hinge region and the ligand binding domain. For this part of the ER we found a wild type mRNA in all 8 meningiomas tested. No mutations were detected. Apart from this transcript we found two alternatively spliced products missing exons 4 and 7, respectively in 8/8 meningioma specimens. These two products were not exclusive for meningioma, since they were also detected in the MCF7 breast cancer cell line which was used as control. ER deletion mutants missing exon 7 have already been reported [Ref. 1; Molec. Endocr. 5 (1991) 1571-1577]. These are dominant negative. To our knowledge, this is the first report on ER mutants missing exon 4. The presence of ER variants missing exon 4, which is probably not able to bind heat shock protein 90 and therefore may be constitutively active, might explain the autonomous expression of PR in meningioma.
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PMID:Wild type and alternatively spliced estrogen receptor messenger RNA in human meningioma tissue and MCF7 breast cancer cells. 849 31

Two populations of the rat uterine estrogen receptor (ER) were separated and characterized using aqueous two-phase partitioning. Countercurrent distribution of rat uterine cytosolic ER allowed rapid and efficient separation of two populations, one population partitioned preferentially into the top phase (T, K(obs) = 3-6) and the other into the bottom phase (B, K(obs) = 0.01-0.03). The majority of unoccupied cytosolic ER is in the T population. Upon estrogen binding and/or heating to 30 degrees C in vitro the T population is converted to the B population. The transition from T to B does not exclusively involve loss of heat shock protein 90 and does not alter the ligand binding ability of the steroid binding domain. Using the human ER steroid binding domain overproduced in Escherichia coli and the steroid binding domain generated by partial trypsinization of the rat uterine ER, we demonstrate that the characteristic distinguishing T and B populations is not localized to this domain alone but may be associated with the amino terminal half of the ER (the A/B and DNA binding domains). The T to B transition of the ER also occurs in human MCF-7 breast cancer cells upon treatment with estrogen at 37 degrees C.
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PMID:Two populations of the estrogen receptor separated and characterized using aqueous two-phase partitioning. 916 96

Autoantibodies to the heat shock protein 90 (Hsp 90) have been reported as prognostic marker in breast cancer patients. Sera from 20 high-grade osteosarcoma patients were tested at the time of diagnosis by enzyme-linked immunosorbent assay. Presence of anti-Hsp90 antibodies correlated with a better response to neoadjuvant chemotherapy (P < 0.01), whereas the absence correlated with development of metastases. These data suggest that anti-Hsp90 antibodies might be of predictive value in human osteosarcoma.
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PMID:Antibodies to heat shock protein 90 in osteosarcoma patients correlate with response to neoadjuvant chemotherapy. 1063 71

Steroid hormone receptors have become an important target in the management of breast cancers. Despite a good initial response rate, however, most tumors become refractory to current hormonal therapies within a year of starting treatment. To address this problem, we evaluated the effects of agents that bind the molecular chaperone heat shock protein 90 (Hsp90) on estrogen receptor function in breast cancer. Unstimulated estrogen and progesterone receptors exist as multimolecular complexes consisting of the hormone-binding protein itself and several essential molecular chaperones including Hsp90. We found that interaction of the Hsp90-binding drugs geldanamycin and radicicol with the chaperone destabilizes these hormone receptors in a ligand-independent manner, leading to profound and prolonged depletion of their levels in breast cancer cells cultured in vitro. Consistent with these findings, in vivo administration of the geldanamycin derivative 17-allylaminogeldanamycin (17AAG; NSC330507) to estrogen-supplemented, tumor-bearing SCID mice resulted in marked depletion of progesterone receptor levels in both uterus and tumor. Drug administration also delayed the growth of established, hormone-responsive MCF-7 and T47D human tumor xenografts for up to 3 weeks after the initiation of therapy. We conclude that in light of their novel mechanism of anti-hormone action, consideration should be given to examining the activity of 17AAG and other Hsp90-binding agents in patients with refractory breast cancer in future clinical trials, either alone or in combination with conventional hormone antagonists.
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PMID:Destabilization of steroid receptors by heat shock protein 90-binding drugs: a ligand-independent approach to hormonal therapy of breast cancer. 1144 26

A novel oxime derivative of radicicol, KF58333, binds to the heat shock protein 90 (Hsp90) and destabilizes its associated signaling molecules. These effects play a critical role in the growth inhibition of tumor cells. To further investigate the effects of this agent, it was administered to two human breast cancer cell lines, KPL-1 and KPL-4, both in vitro and in vivo. KF58333 dose-dependently inhibited the growth and vascular endothelial growth factor (VEGF) secretion, concomitantly with a decrease in VEGF mRNA expression, in each cell line. This agent also suppressed the increase of VEGF secretion and expression induced by hypoxia (1% O(2)). Intravenous injections of this agent into nude mice bearing either KPL-1 or KPL-4 xenografts significantly inhibited the tumor growth associated with a decrease in the Ki67 labeling index and microvascular area and an increase in apoptosis and the necrotic area. These findings indicate that the antitumor activity of this radicicol derivative may be partly mediated by decreasing VEGF secretion from tumor cells and inhibiting tumor angiogenesis. To explore the action mechanisms of the anti-angiogenic effect, the expression level of hypoxia-inducible factor (HIF)-1alpha was investigated. KF58333 provided a significant decrease in the HIF-1alpha protein expression under both normoxic and hypoxic conditions. In contrast, the mRNA expression of HIF-1alpha was not decreased by this agent. It is suggested that the post-transcriptional down-regulation of HIF-1alpha expression by this agent may result in a decrease of VEGF expression and tumor angiogenesis.
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PMID:A radicicol derivative, KF58333, inhibits expression of hypoxia-inducible factor-1alpha and vascular endothelial growth factor, angiogenesis and growth of human breast cancer xenografts. 1174 1

Serological screening of recombinant cDNA expression libraries has been widely used for the identification of tumour antigens in various cancer types. Identification of tumour antigens in ovarian cancer may facilitate the development of vaccine-based therapies and of disease biomarkers. The purpose of our investigation is to identify tumour antigens in ovarian cancer by using the serological analysis of recombinant cDNA expression libraries method. A recombinant ovarian carcinoma cDNA expression library was screened with ascites fluid, pooled from five ovarian cancer patients. Twelve tumour antigens encoded by known genes were isolated, including ribosomal protein S18, heat shock protein 90, JK-recombination signal binding protein, ribonucleoprotein H1, RAN binding protein 7, TG-interacting factor, eukaryotic translation initiation factor p40 subunit, human amyloid precursor protein-binding protein 1, ribosomal protein L8, CDC23, IQ motif containing GTPase activating protein 1, and ribosomal protein L3. Heat shock protein 90 was chosen for further investigation. The prevalence of hsp90 autoantibodies in ovarian cancer was determined with immunoassay. Sera from 22 normal females, 32 from ovarian cancer (22 stage III/IV, 10 stage I/II), 37 colorectal cancer, 13 breast cancer, 10 lung cancer, 20 benign gynaecologic diseases, and 10 benign breast lesions were screened. Seven (32%) stage III/IV ovarian cancer, 1 (10%) stage I/II ovarian cancer, 1 (3%) colorectal cancer, 1 (8%) breast cancer, and 1 (5%) benign gynaecologic disease sera were found to contain hsp90 autoantibodies. These data support the view that hsp90 autoantibodies are frequently found in late stage ovarian cancer. Hsp90 may, therefore, represent a novel biomarker for ovarian cancer and a candidate ovarian cancer vaccine target.
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PMID:Identification of heat shock protein 90 and other proteins as tumour antigens by serological screening of an ovarian carcinoma expression library. 1217 5

It was previously reported that a midregion domain of parathyroid hormone-related protein (PTHrP), that is, [67-86]-amide, is able to restrain growth and promote matrigel penetration by the 8701-BC cell line, derived from a biopsy fragment of a primary ductal infiltrating carcinoma of the human breast, and that cell invasion in vitro is drastically impaired by inactivation of urokinase-plasminogen activator (uPa). In this study we started a more detailed investigation of the possible effects on gene expression arising from the interaction between PTHrP [67-86]-amide and 8701-BC breast cancer cells by a combination of conventional-, differential display-and semi-quantitative multiplex-polymerase chain reaction (PCR) assays. We present here the first evidence that the upregulation of some stress-related genes, most noticeably heat shock factor binding protein-1 (hsbp1) and heat shock protein 90 (hsp-90), is involved in the acquisition of an in vitro more invasive phenotype by cells treated with midregion PTHrP. This is conceivably accomplished by sequestering and inactivating heat shock factor-1 (hsf1) which is able to recognize Ets transcription-factor-binding sites present in some gene promoters, such as those of uPa and matrix metalloprotease-1 (MMP-1). In fact, our data show that incubation of PTHrP [67-86]-amide-treated cells with either antisense hsbp1-oligonucleotide or geldanamycin, an hsp90-inactivating antibiotic, results in downregulation of uPa and upregulation of MMP-1, and in a prominent inhibition of cell invasion in matrigel-containing Transwell chambers. Alternatively, incubation of untreated 8701-BC cells with quercetin, a flavonoid known to decrease the amount of free hsf1, is found to induce upregulation of uPa and downregulation of MMP-1, and an increase of matrigel invasion by cells, thus providing further supporting data of the involvement of hsf unavailability on the modulation of uPa and MMP-1 expression and on cell invasive behaviour. These studies confirm a previous postulate that over-secretion of uPa, rather than of other extracellular proteases, is a primary condition for the increase of invasive activity triggered by PTHrP [67-86]-amide in vitro, and support a role for midregion forms of PTHrP in potentially affecting pathological mammary growth and differentiation. They also identify two new key protagonists in the complex scenario of breast tumor cell invasiveness in vitro, that is, hsbp1 and hsp90, which deserve further and more extensive studies as potential and attractive molecular targets for anti-breast cancer treatments.
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PMID:PTHrP [67-86] regulates the expression of stress proteins in breast cancer cells inducing modifications in urokinase-plasminogen activator and MMP-1 expression. 1272 57

Tamoxifen is the primary hormonal therapy for breast cancer and is also used as a breast cancer chemopreventative agent. A major problem with tamoxifen therapy is undesirable endometrial proliferation. To identify proteins associated with the growth stimulatory effects of tamoxifen in an ER-positive model, the present study profiled total cellular and secreted proteins regulated by estradiol and selective estrogen receptor modifiers (SERMs) in the Ishikawa endometrial adenocarcinoma cell line using two-dimensional gel electrophoresis. Following 24 h incubation with 10(-8) M estradiol, 10(-7) M 4-hydroxytamoxifen, or 10(-7) M EM-652 (Acolbifene), nine proteins exhibited significant increase in expression. The proteins identified were heat shock protein 90-alpha, and -beta, heterogeneous nuclear ribonucleoprotein F, RNA polymerase II-mediating protein, cytoskeletal keratin 8, cytoskeletal keratin 18, ubiquitin-conjugating enzyme E2-18 kDa and nucleoside diphosphate kinase B. These protein profiles may serve as novel indices of SERM response and may also provide insight into novel mechanisms of SERM-mediated growth.
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PMID:Selective estrogen receptor modulator regulated proteins in endometrial cancer cells. 1514 34


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