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)

Early external detection of cancer gene activity might enable early treatment of cancer and might reduce cancer mortality. We hypothesized that oncogene mRNA overexpressed at thousands of copies per malignant cell in a zone of transformed cells could be imaged externally by scintigraphic imaging, PET (positron emission tomography) or MRI (magnetic resonance imaging) with PNA (peptide nucleic acid) hybridization probes that include chelators for metal cations and a cyclized peptide analogue of IGF-1 (insulin-like growth factor 1), D(Cys-Ser-Lys-Cys), to mediate internalization by IGF1R (IGF-1 receptor) overexpressed on cancer cells. We observed that human MCF7 breast cancer cells that overexpress IGF1R efficiently internalized fluorescein-chelator-PNA-D(Cys-Ser-Lys-Cys) to the cytoplasm, but not with D(Cys-Ala-Ala-Cys). Scintigraphic imaging of MCF7 xenografts in immunocompromised mice revealed that CCND1 and MYC [(99m)Tc]chelator-PNA-D(Cys-Ser-Lys-Cys) probes yielded xenograft. PET imaging with [(64)Cu]chelator-PNA-D(Cys-Ser-Lys-Cys) yielded stronger signals. Scintigraphic imaging of human AsPC1 pancreas cancer xenografts with [(99m)Tc]chelator-KRAS PNA-D(Cys-Ser-Lys-Cys) yielded strong xenograft signals. Stronger xenograft image intensities were obtained by PET imaging of [(64)Cu]chelator-KRAS PNA-D(Cys-Ser-Lys-Cys). MRI required extension of chelator-polydiamidopropanoate dendrimers from the N-termini of the PNA probes to increase the number of contrast paramagnetic gadolinium (III) cations per probe. These results provide a basis for detection of oncogene activity in tissues from outside the body by hybridization with metal-chelator-PNA-peptides that are selectively internalized by cancer cells.
 ...
PMID:Receptor-mediated internalization of chelator-PNA-peptide hybridization probes for radioimaging or magnetic resonance imaging of oncogene mRNAs in tumours. 1723 4

WNT family members are secreted-type glycoproteins regulating cell fate, planar cell polarity, cell adhesion, and cell movement. WNT signals are context-dependently transduced to the canonical pathway for the transcriptional up-regulation of MYC, CCND1, FGF20, JAG1, WISP1 and DKK1 genes, and also to the non-canonical pathway for the activation of RHOA, JNK, PKC, NFAT and NLK signaling cascades. We cloned and characterized the wild-type human WNT8B, while another group the aberrant human WNT8B with Gly230Ala and Arg284Leu amino-acid substitutions. Although WNT8B is undetectable in normal adult tissues by using Northern blot analyses, WNT8B is expressed in gastric cancer, pancreatic cancer, colorectal cancer, breast cancer, and embryonal tumors. Here, comparative integromics on WNT8B orthologs were investigated by using bioinformatics (Techint) and human intelligence (Humint). Cow Wnt8b gene was identified within NW_001494361.1 genome sequence. Predicted sequence XM_582222.3 was an artificial cow Wnt8b with aberrant prediction for the first exon. Cow Wnt8b complete coding sequence was found to encode a 350-amino-acid protein, which showed 96.9% total-amino-acid identity with human WNT8B. Comparative proteomics revealed that N-terminal signal peptide, 22 Cys residues, two Asn-linked glycosylation sites, Gly230, and Arg284 of human WNT8B were conserved among mammalian WNT8B orthologs. Comparative genomics revealed that POU/OCT- and GATA-binding sites in the 5'-flanking promoter region were conserved among human, chimpanzee, cow, mouse, and rat WNT8B orthologs. In silico expression analyses revealed that human WNT8B was expressed in embryoid body derived from embryonic stem (ES) cells, hepatocyte progenitors derived from ES cells, fetal brain, diffuse-type gastric cancer, colorectal cancer, prostate cancer, and ovarian fibrotheoma. Based on the expression profiles of POU and GATA family transcription factors, it was revealed that WNT8B expression in hepatocyte progenitors derived from human ES cells is due to POU5F1 (OCT3/OCT4) and GATA3, and also that WNT8B expression in diffuse-type gastric cancer is due to POU5F1 and GATA6.
 ...
PMID:Conserved POU/OCT- and GATA-binding sites in 5'-flanking promoter region of mammalian WNT8B orthologs. 1739 31

Fluorescent (FISH) and chromogenic (CISH) in situ hybridization have recently become part of the diagnostic armamentarium of breast pathologists. HER2 gene testing by FISH and/or CISH has become an integral part of the diagnostic workup for patients with breast cancer. In this era of high throughput technologies, these techniques have proven instrumental for the validation of results from microarray-based comparative genomic hybridization and for the identification of novel oncogenes and tumor suppressor genes. Furthermore, FISH and CISH applied to tissue microarrays have expedited the characterization of genomic changes associated with specific breast cancer molecular subtypes and the identification of novel prognostic and predictive markers. In this review, we provide in this review a critical assessment of CISH and FISH and the impact of the analysis of amplification of specific oncogenes (eg, HER2, EGFR, MYC, CCND1, and FGFR1) and deletion of tumor suppressor genes (eg, BRCA1 and BRCA2) on our understanding of breast cancer.
 ...
PMID:Chromogenic and fluorescent in situ hybridization in breast cancer. 1764 May 50

CSN5 has been implicated as a candidate oncogene in human breast cancers by genetic linkage with activation of the poor-prognosis, wound response gene expression signature. CSN5 is a subunit of the eight-protein COP9 signalosome, a signaling complex with multiple biochemical activities; the mechanism of CSN5 action in cancer development remains poorly understood. Here, we show that CSN5 isopeptidase activity is essential for breast epithelial transformation and progression. Amplification of CSN5 is required for transformation of primary human breast epithelial cells by defined oncogenes. The transforming effects of CSN5 require CSN subunits for assembly of the full COP9 signalosome and the isopeptidase activity of CSN5, which potentiates the transcriptional activity of MYC. Transgenic inhibition of CSN5 isopeptidase activity blocks breast cancer progression evoked by MYC and RAS in vivo. These results highlight CSN5 isopeptidase activity in breast cancer progression, suggesting it as a therapeutic target in aggressive human breast cancers.
 ...
PMID:CSN5 isopeptidase activity links COP9 signalosome activation to breast cancer progression. 1819 46

We developed stromal- and epithelial-specific cre-transgenic mice to directly visualize epithelial-mesenchymal transition (EMT) during cancer progression in vivo. Using three different oncogene-driven mouse mammary tumor models and cell-fate mapping strategies, we show in vivo evidence for the existence of EMT in breast cancer and show that myc can specifically elicit this process. Hierarchical cluster analysis of genome-wide loss of heterozygosity reveals that the incidence of EMT in invasive human breast carcinomas is rare, but when it occurs it is associated with the amplification of MYC. These data provide the first direct evidence for EMT in breast cancer and suggest that its development is favored by myc-initiated events.
 ...
PMID:Direct evidence for epithelial-mesenchymal transitions in breast cancer. 1824 97

Estrogen plus progestin hormone therapy has been associated with increased breast proliferation, breast density, and breast cancer risk in postmenopausal women, beyond that seen with estrogen alone. The goal of this study was to evaluate progestogen effects on gene expression profiles in the breast contributing to this promotional effect. Twenty-five ovariectomized adult female cynomolgus monkeys were given the following treatments (expressed as equivalent doses for women) in a randomized crossover design: (1) placebo; (2) oral estradiol (E2, 1 mg/day); (3) E2 + micronized progesterone (P4, 200 mg/day); and (4) E2 + medroxyprogesterone acetate (MPA, 2.5 mg/day). Treatments were given for two months, and breast biopsies were taken after each treatment period. On microarray analysis E2 + MPA treatment resulted in a greater number of significantly regulated genes compared to E2 + P4 and E2 alone (P < 0.0001). Treatment with E2 alone induced modest effects on select genes related to epidermal growth factor receptor (EGFR) activity which were augmented by the addition of MPA but not P4, consistent with patterns of epithelial cell proliferation. Genes induced by E2 + MPA included the EGFR ligands EGF, TGFA, and AREG, and downstream targets such as STAT5A, STAT5B, SRC, EIF4EBP1, and MYC. Progestogens showed mixed antagonistic effects on E2-induced genes which tended to be greater for P4 than MPA. These findings suggest that a standard dose of oral E2 + MPA has a more pronounced effect on gene expression in the breast compared to E2 alone or E2 + P4 and that promotional effects of E2 + MPA may be mediated in part by increased EGFR activity.
Breast Cancer Res Treat 2009 Mar
PMID:Transcriptional profiles of progestogen effects in the postmenopausal breast. 1840 70

Breast cancer is the second leading cause of cancer deaths and is the most frequently diagnosed cancer in women of industrialized nations. Breast cancer progression is a multistep process involving genetic and epigenetic alterations that drive normal breast cells into highly malignant derivatives with metastatic potential. MYC is a proto-oncogene whose protein product contains a basic helix-loop-helix domain. MYC functions as a transcription factor regulating up to 15% of all human genes. MYC is regulated at multiple levels, and the protein is a downstream effector of several signaling pathways. In breast cancer cells, MYC target genes are involved in cell growth, transformation, angiogenesis and cell-cycle control. BRCA1 is linked to transcriptional regulation through interaction with MYC. Although the relationship between amplification and overexpression is not clearly delineated, MYC amplification is significantly correlated with aggressive tumor phenotypes and poor clinical outcomes. MYC amplification is emerging as an important predictor of response to HER2-targeted therapies and its role in BRCA1-associated breast cancer makes it an important target in basal-like/triple-negative breast cancers.
 ...
PMID:MYC in breast tumor progression. 1892 59

Single markers are insufficient to accurately assess risk of relapse for adjuvant therapy guidance in operable breast cancer patients. In addition, the accuracy and interpretability of current multi-marker tests is generally limited by their simply additive algorithms and their overlap with clinicopathologic risks. Here, we report the development and validation of a nonlinear algorithm that combines protein (ER, PGR, ERBB2, BCL2 and TP53) and genomic (MYC/8q24) markers with standard clinicopathologic features (tumor size, tumor grade and nodal status) into a global risk assessment profile. The algorithm was trained using statistical pattern recognition in 200 stage I-III hormone receptor-positive patients treated with hormone therapy. Continuous risk scores (0-10+) were then generated for 232 independent patients. In hormone therapy-treated patients, the profile achieved a hazard ratio of 6.2 (95% confidence interval [CI], 1.8-20) in high- vs. low-risk groups for time to distant metastasis with the low-risk group having a 10-year metastasis rate of just 4% (95% CI, 0-8%). Similar results were achieved in untreated patients and for disease-specific survival. In multivariate analyses with standard prognostic factors and clinical practice guidelines, the profile was the only significant variable. Furthermore, the profile reclassified as low risk over half of node-negative patients at elevated risk according to the guidelines, which could have spared such patients from unnecessary cytotoxic chemotherapy. It also accurately identified a group of high-risk patients within a guideline low-risk group. In summary, the profile intelligently combines biologically relevant marker pathways and established clinicopathologic risks to help guide breast cancer patients to the most appropriate level of adjuvant therapy.
 ...
PMID:Prognostic marker profile to assess risk in stage I-III hormone receptor-positive breast cancer patients. 1903 52

Tumour cell lines derived from breast cancer patients constitute one of the cornerstones of breast cancer research. To characterise breast cancer cell lines at the genetic level, we have developed a full tiling path bacterial artificial chromosome (BAC) array collection for comparative genomic hybridisation (aCGH). This aCGH BAC collection covers 98% of the entire human genome at a resolution of 40-60 kbp. We have used this platform alongside an in-house produced 17 K cDNA microarray set to characterise the genetic and transcriptomic profiles of 24 breast cancer cell lines, as well as cell types derived from non-diseased breast. We demonstrate that breast cancer cell lines have genomic and transcriptomic features that recapitulate those of primary breast cancers and can be reliably subclassified into basal-like and luminal subgroups. By overlaying aCGH and transcriptomic data, we have identified 753 genes whose expression correlate with copy number; this list comprised numerous oncogenes recurrently amplified and overexpressed in breast cancer (e.g., HER2, MYC, CCND1 and AURKA). Finally, we demonstrate that although breast cancer cell lines have genomic features usually found in grade III breast cancers (i.e., gains of 1q, 8q and 20q), basal-like and luminal cell lines are characterised by distinct genomic aberrations.
Breast Cancer Res Treat 2009 Dec
PMID:A high-resolution integrated analysis of genetic and expression profiles of breast cancer cell lines. 1916 12

Uncontrolled growth of cancer cells can be related to dysfunctional cell cycle control, including entry into S-phase, initiating cell division. Cyclin CCND3 and CCNE1 along with CDK2 and CDK6 regulate this checkpoint, and genetic changes, detectable by fluorescence in situ hybridization, are hypothesized to increase the aggressiveness of breast cancer, thereby influencing patient survival. Genomic change was investigated in 106 primary breast cancer samples, where the combined gene copy number changes in one of these four cell cycle regulatory factors was observed in 22% of the 98 tumors of successful analysis, distributed with 15 deletions and 7 amplifications. A trend towards decreased survival was observed with the aberrations, suggesting a prognostic potential of this set of markers, which was supported by an association with tumor grade. For validation of the new set of FISH probes for the G1/S-phase cell cycle factors, two additional markers, frequently amplified in breast cancers, were included in this study: The G1/S phase control gene CCND1 and the proliferation marker MYC. Both markers were amplified in 14% and deleted in 5% of the cases. This is the first report of genomic deletions of MYC in breast cancer.
 ...
PMID:Frequent amplifications and deletions of G1/S-phase transition genes, CCND1 and MYC in early breast cancers: a potential role in G1/S escape. 1924 61


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