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)

To investigate the effects of estrogen (E2) on telomerase activity and its mechanism in human breast cancer cells, estrogen receptor positive MCF-7 cells were treated with different concentrations of E2. Telomerase activity was measured by using TRAP-ELISA method, the cell cycle phases analyzed by using flow cytometry, and the expression of Cyclin D1 detected by using immunohistochemistry method. The results showed that telomerase activity levels were increased in MCF-7 cells treated with 10(-8) mol/L E2 during the observed period (P < 0.05), and E2 increased telomerase activity levels in a dose-dependent manner(10(-10)-10(-8) mol/L); Simultaneously, the cell cycle phases of MCF-7 cells treated with 10(-8) mol/L E2 were changed significantly: G0/G1 phase decreased from 60.52% to 50.93%. S phase increased from 29.03% to 30.83%; However, the expression of Cyclin D1 was decreased. It was concluded that estrogen can upregulate telomerase activity of MCF-7 cells, and the effect can be blocked by antiestrogen tamoxifen. Its mechanism may be closely associated with modulation of cell cycle phases.
 ...
PMID:Effect of estrogen on telomerase activity in human breast cancer cells. 1452 36

We applied comparative genomic hybridization (CGH) to 46 breast carcinoma samples, collected from 1993 to 1995, in order to detect chromosome 1q gains and 16q losses and to define whether samples showing both these alterations had distinct biopathologic features and different clinical outcome. A total of 22 samples (48%) had simultaneous chromosome 1q gain and 16q loss, which was always associated with other genetic changes. In total, 23 samples had various chromosome imbalances (including chromosome 1q gain independent of chromosome 16q loss and vice versa) and one sample did not show detectable alterations. Samples having chromosome 1q gain/16q loss were compared to the other samples with regard to neoplasm size, lymph-node status, histologic and nuclear grade, estrogen and progesterone receptor presence, Ki-67, pRB, Cyclin D1, Cyclin A, p53, p21 and p27 expression as detected by immunohistochemistry. The samples showing chromosome 1q gain/16q loss had high steroid hormone receptor expression (P=0.02), low cell growth fraction (Ki-67, P=0.03) and high p27 expression (P<0.001). No statistical correlation with disease-free survival and overall survival or response to hormonal therapy was found. We conclude that simultaneous chromosome 1q gain/16q loss is a frequent event in invasive breast cancer, which occurs in a subset of both intermediate- and high-grade breast carcinomas. Although the final chromosome 1q and 16q imbalances might have originated from different chromosome alterations in low- and high-grade samples, the gene-dosage effect might be important in conferring peculiar biopathologic characteristics to this subset of samples. The cytogenetic and molecular mechanisms underlying these chromosome changes deserve further investigations.
 ...
PMID:Simultaneous chromosome 1q gain and 16q loss is associated with steroid receptor presence and low proliferation in breast carcinoma. 1497 37

Mitogenic growth factor- and integrin-dependent signaling pathways cooperate to control the proliferation of nontransformed cells. As integral mediators of these networks, the Rho family of GTPases play a pivotal role in G1 cell cycle progression, primarily through regulation of cyclin D1 expression, as well as the levels of the cyclin-dependent kinase inhibitors p21cip1 and p27kip1. Such dual control of both the critical positive and negative regulators of G1 progression make the Rho GTPases prime candidates to target the autonomous proliferation which typifies cancer cells. Cyclin D1 has been identified as an important oncogene and the cdk inhibitors as tumor suppressors in human breast carcinogenesis. Evidence pointing to the potential role of Rho-dependent pathways and their interaction with oncogenic Ras in contributing to such cell cycle abnormalities that characterize human breast cancer is also presented.
Breast Cancer Res Treat 2004 Mar
PMID:Rho GTPases as key transducers of proliferative signals in g1 cell cycle regulation. 1499 52

Previous studies have suggested that cells may differ in their response to metal stress. This study was undertaken to investigate the role of PI3K/Akt signaling pathway in metal resistance in human breast cancer epithelial cells with different p53 and estrogen receptor status. Exposure to copper and zinc increased Akt phosphorylation with its nuclear localization only in MDA-MB-231 cells with no estrogen receptor and mutated p53. Cyclin D1 expression and cell-cycle progression followed the metal-induced Akt phosphorylation. Treatment with LY294002 abrogated these effects, suggesting the essential role of PI3-kinase. In contrast, in MCF-7 cells with wild type p53 and estrogen receptor, there was no change in Akt activation, while suppression of p53 activity by pifithrin-alpha increased phosphorylation of Akt after the treatment with copper. In MCF-7 cells, the metal treatment increased the phosphorylation of p53 at serine 15, up-regulated p21 expression, and resulted in cell-cycle arrest in G1 phase with apoptosis. These results demonstrate that copper-induced apoptosis in MCF-7 cells is p53 dependent, whereas the metal resistance in MDA-MB-231 cells may be due to activation of Akt in the absence of a functional p53.
 ...
PMID:Differential regulation of signal transduction pathways in wild type and mutated p53 breast cancer epithelial cells by copper and zinc. 1500 99

The D-type and E-type cyclins control the G(1) to S phase transition during normal cell cycle progression and are critical components of steroid- and growth factor-induced mitogenesis in breast epithelial cells. Mammary epithelial cell-specific overexpression of these genes leads to mammary carcinoma, while in cyclin D1-deficient mice mammary gland development is arrested prior to lobuloalveolar development. Cyclin D1 null mice are resistant to mammary carcinoma induced by the neu and ras oncogenes, indicating an essential role for cyclin D1 in the development of some mammary cancers. Cyclin D1 and E1 are commonly overexpressed in primary breast cancer, with some evidence of an association with an adverse patient outcome. This observation may result in part from their ability to confer resistance to endocrine therapies. The functional consequences of cyclin E overexpression in breast cancer are likely related to its role in cell cycle progression, whereas that of cyclin D1 may also be a consequence of a more recently defined role in transcriptional regulation.
 ...
PMID:Cyclins and breast cancer. 1508 21

Clinical data and samples from patients diagnosed, more than 10 years previously, with operable node-negative breast cancer (participants in the Scottish Adjuvant Tamoxifen trial), were revisited. Cases with two distinct categories of outcome were selected; more than 10 years disease-free survival ('good outcome') or distant relapse within 6 years of diagnosis ('poor outcome'). An initial set of cases was analysed for a range of putative prognostic markers and a prognostic index, distinguishing the two outcome categories, was calculated. This index was then validated by testing its predictive power on a second, independent set of cases. A combination of histological grade plus immunochemical staining for BCL-2, p27 and Cyclin D1, generated a useful prognostic index for tamoxifen-treated patients but not for those treated by surgery alone. The value of the index was confirmed in a second set of tamoxifen-treated, early stage breast cancers. Overall, it correctly predicted good and poor outcome in 79 and 74% of cases, respectively (odds ratio 11.0). Other markers assessed added little to prediction of outcome. In the case of molecular assays, sensitivity and reliability were compromised by the age of the tissue specimens and the variability of fixation protocols. In selecting patients for adjuvant systemic chemotherapy, the proposed index improves considerably on current international guidelines and matches the performance reported for 'gene-expression signature' analysis.
 ...
PMID:A prognostic index for operable, node-negative breast cancer. 1513 74

The Ink4a/Arf locus encodes two structurally unrelated tumor suppressor proteins, p16(INK4a) and p14(ARF) (murine p19(ARF)). Invariant inactivation of either the p16(INK4a)-cyclin D/CDK-pRb pathway and/or p53-p14(ARF) pathway occurs in most human tumors. Cyclin D1 is frequently overexpressed in breast cancer cells contributing an alternate mechanism inactivating the p16(INK4a)/pRb pathway. Targeted overexpression of cyclin D1 to the mammary gland is sufficient for tumorigenesis, and cyclin D1-/- mice are resistant to Ras-induced mammary tumors. Recent studies suggest cyclin D1 and p16(INK4a) expression are reciprocal in human breast cancers. Herein, reciprocal regulation of cyclin D1 and p16(INK4a) was observed in tissues of mice mutant for the Ink4a/Arf locus. p16(INK4a) and p19(ARF) inhibited DNA synthesis in MCF7 cells. p16(INK4a) repressed cyclin D1 expression and transcription. Repression of cyclin D1 by p16(INK4a) occurred independently of the p16(INK4a)-cdk4-binding function and required a cAMP-response element/activating transcription factor-2-binding site. p19(ARF) repressed cyclin D1 through a novel distal cis-element at -1137, which bound p53 in chromatin-immunoprecipitation assays. Transcriptional repression of the cyclin D1 gene through distinct DNA sequences may contribute to the tumor suppressor function of the Ink4a/Arf locus.
 ...
PMID:The inhibitor of cyclin-dependent kinase 4a/alternative reading frame (INK4a/ARF) locus encoded proteins p16INK4a and p19ARF repress cyclin D1 transcription through distinct cis elements. 1520 22

In this study, the MCF-7 breast cancer cells that lack caspase-3 were transfected with a wild type (WT) or mutant caspase-3 cDNA. Expression of the WT, but not of the mutant, caspase-3 was associated with increased caspase activity and susceptibility to staurosporine (STS)-induced apoptosis. Both derivatives displayed inhibition of cell growth compared with vector control cells. Growth inhibition was associated with increased expression of the cyclin dependent kinase (CDK) inhibitor p27Kip1 in the WT, but not in the mutant caspase-3 expressing cells. Cyclin D1 expression level was not affected by caspase-3 expression. Phosphorylation of the Akt protein was decreased in both WT and mutant caspase transfected cells, although Akt expression level remained unchanged. These results suggest that caspase-3 might have biological functions independent of its protease activity and that its loss might contribute to tumor development by increasing the growth potential of cancer cells.
 ...
PMID:Caspase-3 inhibits the growth of breast cancer cells independent of protease activity. 1531 34

Cyclin D1 encodes the regulatory subunit of a holoenzyme that phosphorylates and inactivates the retinoblastoma protein and promotes progression through the G1-S phase of the cell cycle. Amplification or overexpression of cyclin D1 plays pivotal roles in the development of a subset of human cancers including parathyroid adenoma, breast cancer, colon cancer, lymphoma, melanoma, and prostate cancer. Of the three D-type cyclins, each of which binds cyclin-dependent kinase (CDK), it is cyclin D1 overexpression that is predominantly associated with human tumorigenesis and cellular metastases. In recent years accumulating evidence suggests that in addition to its original description as a CDK-dependent regulator of the cell cycle, cyclin D1 also conveys cell cycle or CDK-independent functions. Cyclin D1 associates with, and regulates activity of, transcription factors, coactivators and corepressors that govern histone acetylation and chromatin remodeling proteins. The recent findings that cyclin D1 regulates cellular metabolism, fat cell differentiation and cellular migration have refocused attention on novel functions of cyclin D1 and their possible role in tumorigenesis. In this review, both the classic and novel functions of cyclin D1 are discussed with emphasis on the CDK-independent functions of cyclin D1.
 ...
PMID:Minireview: Cyclin D1: normal and abnormal functions. 1533 80

Cancer is a genetic disease. Breast cancer tumorigenesis can be described as a multi-step process in which each step is thought to correlate with one or more distinct mutations in major regulatory genes. The question addressed is how far a multi-step progression model for sporadic breast cancer would differ from that for hereditary breast cancer. Hereditary breast cancer is characterized by an inherited susceptibility to breast cancer on basis of an identified germline mutation in one allele of a high penetrance susceptibility gene (such as BRCA1, BRCA2, CHEK 2, TP53 or PTEN). Inactivation of the second allele of these tumour suppressor genes would be an early event in this oncogenic pathway (Knudson's "two-hit" model). Sporadic breast cancers result from a serial stepwise accumulation of acquired and uncorrected mutations in somatic genes, without any germline mutation playing a role. Mutational activation of oncogenes, often coupled with non-mutational inactivation of tumour suppressor genes, is probably an early event in sporadic tumours, followed by more, independent mutations in at least four or five other genes, the chronological order of which is likely less important. Oncogenes that have been reported to play an early role in sporadic breast cancer are MYC, CCND1 (Cyclin D1) and ERBB2 (HER2/neu). In sporadic breast cancer, mutational inactivation of BRCA1/2 is rare, as inactivation requires both gene copies to be mutated or totally deleted. However, non-mutational functional suppression could result from various mechanisms, such as hypermethylation of the BRCA1 promoter or binding of BRCA2 by EMSY. In sporadic breast tumorigenesis, at least three different pathway-specific mechanisms of tumour progression are recognizable, with breast carcinogenesis being different in ductal versus lobular carcinoma, and in well differentiated versus poorly differentiated ductal cancers. Thus, different breast cancer pathways emerge early in the process of carcinogenesis, ultimately leading to clinically different tumour types. As mutations acquired early during tumorigenesis will be present in all later stages, large-scale gene expression profiling using DNA microarray analysis techniques can help to classify breast cancers into clinically relevant subtypes.
 ...
PMID:Oncogenic pathways in hereditary and sporadic breast cancer. 1943 86


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