• Humans
• Polymorphism, Single Nucleotide
• Neoplasms/genetics
• Transcription Factors/genetics
• Gene Expression Regulation, Neoplastic
• DNA Copy Number Variations
• DNA Methylation
• RNA, Long Noncoding/genetics
• MicroRNAs/genetics

• Humans
• Receptors, Chimeric Antigen/genetics
• Immunotherapy, Adoptive/adverse effects
• Multiple Myeloma/therapy
• Multiple Myeloma/complications
• Tumor Suppressor Protein p53/genetics
• B-Cell Maturation Antigen/immunology
• Male
• CD4-Positive T-Lymphocytes
• Lymphoma, T-Cell/genetics
• Lentivirus/genetics
• Cell Transformation, Neoplastic/genetics
• Middle Aged

• P30 CA008748 NCI NIH HHS
• R01 CA241762 NCI NIH HHS

• Arsenic
• Hepatic injury
• Tauroursodeoxycholic acid
• transcriptomics

• Animals
• Taurochenodeoxycholic Acid/pharmacology
• Mice
• Mice, Inbred C57BL
• Arsenic/toxicity
• Chemical and Drug Induced Liver Injury/metabolism
• Chemical and Drug Induced Liver Injury/genetics
• Gene Expression Profiling
• Male
• Transcriptome/drug effects
• Liver/drug effects
• Liver/metabolism
• Liver/pathology

• Colorectal cancer
• HnRNPD
• LOC101927668
• RBM47/p53/p21 signaling

• Humans
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• RNA, Long Noncoding/genetics
• RNA, Long Noncoding/metabolism
• Mice
• Animals
• Signal Transduction
• Tumor Suppressor Protein p53/metabolism
• Tumor Suppressor Protein p53/genetics
• Disease Progression
• RNA-Binding Proteins/metabolism
• RNA-Binding Proteins/genetics
• Cell Proliferation
• Female
• Cell Line, Tumor
• DNA Copy Number Variations
• Male
• Gene Expression Regulation, Neoplastic
• Cyclin-Dependent Kinase Inhibitor p21/metabolism
• Cyclin-Dependent Kinase Inhibitor p21/genetics
• Mice, Nude

• bladder cancer
• high grade
• low grade
• methylation
• recurrence

• MDM2
• MDMX
• apoptosis
• cancer treatment
• cell competition
• cell-cycle arrest
• ferroptosis
• genome stability
• immunity
• metabolism
• metastasis
• p53
• p53 mutation
• p63
• p73
• senescence
• stem cell dynamics
• targeting p53
• tumor suppression

• Humans
• Tumor Suppressor Protein p53/metabolism
• Tumor Suppressor Protein p53/genetics
• Neoplasms/genetics
• Neoplasms/metabolism
• Neoplasms/pathology
• Animals
• Ferroptosis/genetics
• Signal Transduction
• Apoptosis
• Protein Processing, Post-Translational

• R01 CA254970 NCI NIH HHS
• R01 CA258390 NCI NIH HHS
• R35 CA253059 NCI NIH HHS

• 82173893 National Natural Science Foundation of China (National Science Foundation of China)
• LQ22H310002 Natural Science Foundation of Zhejiang Province (Zhejiang Provincial Natural Science Foundation)

• Apoptosis
• Carbendazim
• Chitosan nanoparticles
• Gene regulation
• Immunohistochemistry

• 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine
• 7,12-dimethylbenz[a]anthracene
• HRas proto-oncogene
• ductal carcinoma
• mammary glands
• mice
• myoepithelioma
• tumor protein p53

• Colorectal cancer
• Genetics
• Mutations
• NGS
• Oligo-metastases

Pevonedistat is a neddylation inhibitor that blocks proteasomal degradation of cullin–RING ligase (CRL) proteins involved in the degradation of short-lived regulatory proteins, including those involved with cell-cycle regulation. We determined the sensitivity and mechanism of action of pevonedistat cytotoxicity in neuroblastoma. Pevonedistat cytotoxicity was assessed using cell viability assays and apoptosis. We examined mechanisms of action using flow cytometry, bromodeoxyuridine (BrDU) and immunoblots. Orthotopic mouse xenografts of human neuroblastoma were generated to assess in vivo anti-tumor activity. Neuroblastoma cell lines were very sensitive to pevonedistat (IC50 136–400 nM). The mechanism of pevonedistat cytotoxicity depended on p53 status. Neuroblastoma cells with mutant (p53^MUT) or reduced levels of wild-type p53 (p53si-p53) underwent G2-M cell-cycle arrest with rereplication, whereas p53 wild-type (p53^WT) cell lines underwent G0-G1 cell-cycle arrest and apoptosis. In orthotopic neuroblastoma models, pevonedistat decreased tumor weight independent of p53 status. Control mice had an average tumor weight of 1.6 mg + 0.8 mg versus 0.5 mg + 0.4 mg (p < 0.05) in mice treated with pevonedistat. The mechanism of action of pevonedistat in neuroblastoma cell lines in vitro appears p53 dependent. However, in vivo studies using mouse neuroblastoma orthotopic models showed a significant decrease in tumor weight following pevonedistat treatment independent of the p53 status. Novel chemotherapy agents, such as the NEDD8-activating enzyme (NAE) inhibitor pevonedistat, deserve further study in the treatment of neuroblastoma.

• cell cycle
• cullin–ring ligase
• pevonedistat
• rereplication
• ubiquitination
• xenograft

• DEHP
• female germ cell
• granulosa cell
• primordial follicle assembly
• single-cell transcriptome

• Chromosomal instability
• Epstein-Barr virus
• Gastric cancer
• Microsatellite instability
• p53

• CRISPR-Cas9
• P53
• RNA sequencing
• mRNA
• miRNA
• mutation

• Mouse models
• Myc addiction
• Polycystin
• Renal development
• p53-dependent annihilation

• Cancer
• Vitamin D
• Vitamin D receptor
• p53

• Context-specific networks
• Network biology
• Protein network
• Protein–protein interactions
• Systems biology

• Computational Biology/methods
• Databases, Protein
• Humans
• Protein Interaction Mapping
• Protein Interaction Maps
• Proteins/chemistry
• Proteins/metabolism
• Systems Biology/methods

Cellular senescence, a term originally used to define the characteristics of normal human fibroblasts that reached their replicative limit, is an important factor for ageing, age-related diseases including cancer, and cell reprogramming. These outcomes are mediated by senescence-associated changes in gene expressions, which sometimes lead to the secretion of pro-inflammatory factors, or senescence-associated secretory phenotype (SASP) that contribute to paradoxical pro-tumorigenic effects. p53 functions as a transcription factor in cell-autonomous responses such as cell-cycle control, DNA repair, apoptosis, and cellular senescence, and also non-cell-autonomous responses to DNA damage by mediating the SASP function of immune system activation. The human TP53 gene encodes twelve protein isoforms, which provides an explanation for the pleiotropic p53 function on cellular senescence. Recent reports suggest that some short isoforms of p53 may modulate gene expressions in a full-length p53-dependent and -independent manner, in other words, some p53 isoforms cooperate with full-length p53, whereas others operate independently. This review summarizes our current knowledge about the biological activities and functions of p53 isoforms, especially Δ40p53, Δ133p53α, and p53β, on cellular senescence, ageing, age-related disorder, reprogramming, and cancer. Numerous cellular and animal model studies indicate that an unbalance in p53 isoform expression in specific cell types causes age-related disorders such as cancer, premature ageing, and degenerative diseases.

• ageing and age-related diseases
• cancer
• cellular senescence
• p53 isoform
• reprogramming

• Aging
• Animals
• Cellular Reprogramming
• Cellular Senescence
• Genes, p53
• Humans
• Neoplasms/genetics
• Neoplasms/metabolism
• Protein Isoforms/genetics
• Protein Isoforms/metabolism
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism

The knowledge about specific mechanisms generating TP53 dysfunction in diffuse large B-cell lymphoma is limited. The aim of the current study was to comprehensively explore TP53 gene variability resulting from somatic mutations, promoter methylation, and allelic imbalance in tumorous tissue of diffuse large B-cell lymphoma (DLBCL).

DNA samples from 74 patients with DLBCL were used. Genomic DNA was isolated from paraffin blocks of lymph nodes or from extranodal biopsies of tumors by the phenol–chloroform extraction method with guanidine. Analysis of coding sequences of the TP53 gene was based on Sanger’s direct sequencing method. The methylation status of the TP53 promoter was analyzed using by methylation-specific PCR on bisulfite-converted DNA. Assessment of the detected mutations was carried out in the IARC TP53 Database and the TP53 UMD mutation database of human cancer.

The mutations in regions coding for the DNA-binding domain were prevalent (95%). In the analyzed sample of patients, codons 275, 155, 272, and 212 were hotspots of mutations in the TP53 gene. In addition, functionally significant intron mutations (IVS6-36G > C and IVS5 + 43G > T) were detected. Instances of TP53 promoter methylation were observed only in a few samples of diffuse large B-cell lymphoma tissue. Furthermore, loss of heterozygosity was revealed only in the subgroup of patients with altered status of the gene (mutations were detected in five patients and promoter methylation in one case).

Thus, the results suggest that there are two sequential events in the formation of diffuse large B-cell lymphoma in at least some cases. The first event is mutation or methylation of the TP53 promoter, leading to appearance of a cell with increased risk of malignant transformation. The second event is the loss of an intact allele of the gene; this change is necessary for tumorigenesis. We identified TP53 mutation patterns in a Russian cohort of patients with de novo DLBCL who were treated with R-CHOP and R-CHOP-like regimens and confirmed that TP53 mutation status is a valuable prognostic biomarker.

• Allelic imbalance
• Diffuse large B-cell lymphoma
• Intron mutations
• Methylation
• Sequencing
• TP53 gene

Annexin A2 has been involved in cancer cell adhesion, invasion and metastasis. However, the exact function and mechanism of Annexin A2 in tumor progression of NSCLCs have not been elucidated. In this study, we showed that Annexin A2 was evidently overexpressed in human NSCLCs cell lines and NSCLCs tissues. Clinicopathologic analysis showed that Annexin A2 expression was significantly correlated with clinical stage, and lymph node metastasis. Kaplan-Meier analysis revealed that patients with high Annexin A2 expression had poorer overall survival rates than those with low Annexin A2 expression. Moreover, we found that knockdown of Annexin A2 significantly suppressed cell proliferation and invasion of NSCLCs cells. Mechanistically, our studies showed that knockdown of Annexin A2 increased the expression of p53, which in turn, induced cell cycle G2 arrest and inhibited epithelial-to-mesenchymal transition (EMT). Taken together, these data suggest that Annexin A2 plays an important role in NSCLCs progression, which could serve as a potential prognosis marker and a novel therapeutic target for NSCLCs.

• Annexin A2
• NSCLCs
• cell proliferation
• epithelial-to-mesenchymal transition
• p53

• HBXIP
• MCF-7 cells
• MDM2
• cancer xenograft nude mice.
• cell proliferation
• human breast cancer
• miR-18b
• p53
• pAKT

• TP53
• adenocarcinoma
• genetic
• noncoding RNA
• promoter regions
• transcription

• Anisomycin
• Apoptosis
• PC12 cell line
• p53 protein

• Oncogene
• cancer
• driver gene
• driver mutation
• tumor suppressor

• GSK-3β
• epidermal growth factor receptor (EGFR)
• forkhead box P3 (FOXP3)
• glycogen synthase kinase 3 (GSK-3)
• lung adenocarcinoma
• phosphorylation
• protein degradation
• protein phosphorylation
• regulatory T cells
• ubiquitylation (ubiquitination)

• DNA adduct formation
• PhIP
• carcinogen metabolism
• cytochrome P450
• heterocyclic aromatic hydrocarbon
• mass spectrometry
• mouse model
• sulfotransferases
• tumor suppressor p53

• Activation, Metabolic/physiology
• Animals
• Blotting, Western
• Carcinogens/metabolism
• Carcinogens/toxicity
• Chromatography, Liquid
• DNA Adducts/metabolism
• Imidazoles/metabolism
• Imidazoles/toxicity
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Tandem Mass Spectrometry
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism

• 14329 Cancer Research UK
• 101126/Z/13/Z Wellcome Trust
• 101126/B/13/Z Wellcome Trust
• C313/A14329 Cancer Research UK

High throughput technologies have been used to profile genes in multiple different dimensions, such as genetic variation, copy number, gene and protein expression, epigenetics, metabolomics. Computational analyses often treat these different data types as independent, leading to an explosion in the number of features making studies under-powered and more importantly do not provide a comprehensive view of the gene’s state. We sought to infer gene activity by integrating different dimensions using biological knowledge of oncogenes and tumor suppressors.

This paper proposes an integrative model of oncogene and tumor suppressor activity in cells which is used to identify cancer drivers and compute patient-specific gene activity scores. We have developed a Fuzzy Logic Modeling (FLM) framework to incorporate biological knowledge with multi-omics data such as somatic mutation, gene expression and copy number measurements. The advantage of using a fuzzy logic approach is to abstract meaningful biological rules from low-level numerical data. Biological knowledge is often qualitative, thus combining it with quantitative numerical measurements may leverage new biological insights about a gene’s state. We show that the oncogenic and altered tumor suppressing state of a gene can be better characterized by integrating different molecular measurements with biological knowledge than by each data type alone. We validate the gene activity score using data from the Cancer Cell Line Encyclopedia and drug sensitivity data for five compounds: BYL719 (PIK3CA inhibitor), PLX4720 (BRAF inhibitor), AZD6244 (MEK inhibitor), Erlotinib (EGFR inhibitor), and Nutlin-3 (MDM2 inhibitor). The integrative score improves prediction of drug sensitivity for the known drug targets of these compounds compared to each data type alone. The gene activity scores are also used to cluster colorectal cancer cell lines. Two subtypes of CRCs were found and potential cancer drivers and therapeutic targets for each of the subtypes were identified.

We propose a fuzzy logic based approach to infer gene activity in cancer by integrating numerical data with descriptive biological knowledge. We compute general patient-specific gene-level scores useful to determine the oncogenic or tumor suppressor status of cancer gene drivers and to cluster or classify patients.

The online version of this article (doi:10.1186/s12918-016-0260-9) contains supplementary material, which is available to authorized users.

• Apoptosis
• Skeletal muscle
• Testosterone
• p53
• p66Shc

• Animals
• Apoptosis/drug effects
• Cell Line
• DNA Fragmentation/drug effects
• Enzyme Activation/drug effects
• Gene Expression Regulation/drug effects
• Humans
• Hydrogen Peroxide/pharmacology
• JNK Mitogen-Activated Protein Kinases/metabolism
• Mice
• Mitochondrial Membrane Transport Proteins/chemistry
• Mitochondrial Membrane Transport Proteins/metabolism
• Mitochondrial Permeability Transition Pore
• Muscle, Skeletal/cytology
• Oxidative Stress/drug effects
• Protein Conformation/drug effects
• Protein Kinase C beta/metabolism
• Protein Transport/drug effects
• Src Homology 2 Domain-Containing, Transforming Protein 1/genetics
• Src Homology 2 Domain-Containing, Transforming Protein 1/metabolism
• Testosterone/pharmacology
• Time Factors
• Tumor Suppressor Protein p53/metabolism

A major problem in identifying the best therapeutic targets for cancer is the molecular heterogeneity of the disease. Cancer is often caused by an accumulation of mutations which produce irreversible damage to the cell’s control mechanisms of survival and proliferation. Different mutations may affect these cellular anachronisms through a combination of molecular interactions which may be dynamically changing during cancer progression. It has been previously shown that cancer accumulates mutations over time. In this paper we address the problem of cancer heterogeneity by modeling cancer progression using somatic mutation and gene expression cross-sectional data.

We propose a novel formulation of integrating somatic mutation and gene expression data to infer the temporal sequence of events from cross-sectional data. Using a mixed integer linear program we model the interaction between groups of different mutated genes and the resulting modifications at the gene expression level. Our approach identifies a partition of mutation events which gradually produce gene expression changes to a partition of genes over time. The proposed formulation is tested using both simulated data and real breast cancer data with matched somatic mutations and gene expression measurements from The Cancer Genome Atlas. First, we classify the genes as oncogenes or tumor suppressors based on the frequency of driver mutations. As expected, the most frequently mutated genes in breast cancer are PIK3CA and TP53 genes. Then, we select those genes with most frequent driver mutations and a set of genes known to play roles in cancer development. Furthermore, we apply the proposed mixed integer linear program to identify the temporal order in which genes mutate and, simultaneously, the changes they produce at the gene expression level during cancer progression. In addition, we are able to identify known causal relationships between mutations and gene expression changes in PI3K/AKT and TP53 pathways.

This paper proposes a new model to infer the temporal sequence in which mutations occur and lead to changes at the gene expression level during cancer progression. The approach is general and can be applied to any data sets with available somatic mutations and gene expression measurements.

The online version of this article (doi:10.1186/s12918-016-0255-6) contains supplementary material, which is available to authorized users.

The folding of newly synthesized proteins and the maintenance of pre-existing proteins are essential in sustaining a living cell. A network of molecular chaperones tightly guides the folding, intracellular localization, and proteolytic turnover of proteins. Many of the key regulators of cell growth and differentiation have been identified as clients of molecular chaperones, which implies that chaperones are potential mediators of oncogenesis. In this review, we briefly provide an overview of the role of chaperones, including HSP70 and HSP90, in cancer. We further summarize and highlight the emerging the role of chaperonin TRiC (T-complex protein-1 ring complex, also known as CCT) in the development and progression of cancer mediated through its critical interactions with oncogenic clients that modulate growth deregulation, apoptosis, and genome instability in cancer cells. Elucidation of how TRiC modulates the folding and function of oncogenic clients will provide strategies for developing novel cancer therapies.

• HSP70/90
• TRiC/CCT
• chaperone
• chaperonin
• oncogenesis
• oncoprotein
• protein-folding
• proteostasis

• Apoptosis
• Carcinogenesis/genetics
• Carcinogenesis/metabolism
• Carcinogenesis/pathology
• Chaperonin Containing TCP-1/genetics
• Chaperonin Containing TCP-1/metabolism
• Disease Progression
• Gene Expression Regulation, Neoplastic
• Genomic Instability
• HSP70 Heat-Shock Proteins/genetics
• HSP70 Heat-Shock Proteins/metabolism
• HSP90 Heat-Shock Proteins/genetics
• HSP90 Heat-Shock Proteins/metabolism
• Humans
• Neoplasm Proteins/chemistry
• Neoplasm Proteins/genetics
• Neoplasm Proteins/metabolism
• Neoplasms/genetics
• Neoplasms/metabolism
• Neoplasms/pathology
• Protein Conformation
• Protein Folding
• Signal Transduction

• P41 GM103832 NIGMS NIH HHS
• PN2 EY016525 NEI NIH HHS
• P41GM103832 NIGMS NIH HHS
• PN2EY016525 NEI NIH HHS

SERPINA1 is the gene for alpha-1 antitrypsin (AAT), an acute phase protein with anti-protease and immunoregulatory activities. Mutations in SERPINA1 gene cause AAT deficiency and predispose individuals to early-onset emphysema and liver diseases. Expression of the SERPINA1 gene is regulated by different promoters and alternative splicing events among non-coding exons 1A, 1B and 1C.

We have developed three quantitative PCR (QT-PCR) assays (1A, 1B and 1C). These assays were applied for the analysis of SERPINA1 alternative transcripts in: (1) 16 human tissues and (2) peripheral blood leukocytes from 33 subjects with AAT mutations and 7 controls.

Tissue-specific expression was found for the SERPINA1 transcripts. The 1A transcripts were mainly expressed in leukocytes and lung tissue while those detected with the 1B assay were highly restricted to leukocytes. Only 1B transcripts significantly correlated with serum AAT levels. The 1C transcripts were specifically found in lung, liver, kidney and pancreas. Furthermore, the expression of transcripts was related to AAT genotypes. While deficient variants of AAT had no pronounced effect on the transcript expression, null alleles were associated with significant reduction of different transcripts.

The possibility to discriminate between SERPINA1 alternative splicing products will help us to understand better the regulation of SERPINA1 gene and its association with SERPINA1 mutations-related diseases.

The online version of this article (doi:10.1186/s12967-015-0585-y) contains supplementary material, which is available to authorized users.

• Animals
• Cell Death
• Cell Survival
• Humans
• Tumor Suppressor Protein p53/metabolism

• 18274 Cancer Research UK
• C596/A10419 Cancer Research UK

Ionizing radiation is a potent activator of the tumor suppressor gene p53, which itself regulates the transcription of genes involved in canonical pathways such as the cell cycle, DNA repair and apoptosis as well as other biological processes like metabolism, autophagy, differentiation and development. In this study, we performed a meta-analysis on gene expression data from different in vivo and in vitro experiments to identify a signature of early radiation-responsive genes which were predicted to be predominantly regulated by p53. Moreover, we found that several genes expressed different transcript isoforms after irradiation in a p53-dependent manner. Among this gene signature, we identified novel p53 targets, some of which have not yet been functionally characterized. Surprisingly, in contrast to genes from the canonical p53-regulated pathways, our gene signature was found to be highly enriched during embryonic and post-natal brain development and during in vitro neuronal differentiation. Furthermore, we could show that for a number of genes, radiation-responsive transcript variants were upregulated during development and differentiation, while radiation non-responsive variants were not. This suggests that radiation exposure of the developing brain and immature cortical neurons results in the p53-mediated activation of a neuronal differentiation program. Overall, our results further increase the knowledge of the radiation-induced p53 network of the embryonic brain and provide more evidence concerning the importance of p53 and its transcriptional targets during mouse brain development.

• Alternative splicing
• Development
• Embryonic brain
• Ionizing radiation
• Neuronal differentiation
• p53 targets

• 3T3-L1 Cells
• Adipose Tissue/cytology
• Animals
• Aromatase/genetics
• Aromatase/metabolism
• Breast/cytology
• Breast/metabolism
• Breast Neoplasms/genetics
• Breast Neoplasms/pathology
• Dinoprostone/genetics
• Dinoprostone/metabolism
• Estrogens/metabolism
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• Obesity/genetics
• Obesity/pathology
• Promoter Regions, Genetic
• Stromal Cells/metabolism
• Stromal Cells/pathology
• Tumor Suppressor Protein p53/biosynthesis

Tumor suppressor molecules play a pivotal role in regulating DNA repair, cell proliferation, and cell death, which are also important processes in the pathogenesis of Alzheimer’s disease. Alzheimer’s disease is the most common neurodegenerative disorder, however, the precise molecular events that control the death of neuronal cells are unclear. Recently, a fundamental role for tumor suppressor molecules in regulating neurons in Alzheimer’s disease was highlighted. Generally, onset of neurodegenerative diseases including Alzheimer’s disease may be delayed with use of dietary neuro-protective agents against oxidative stresses. Studies suggest that dietary antioxidants are also beneficial for brain health in reducing disease-risk and in slowing down disease-progression. We summarize research advances in dietary regulation for the treatment of Alzheimer’s disease with a focus on its modulatory roles in BRCA1 and p53 tumor suppressor expression, in support of further therapeutic research in this field.

• Alzheimer Disease/metabolism
• Alzheimer Disease/pathology
• BRCA1 Protein/metabolism
• DNA Damage
• DNA Repair
• Humans
• Neurons/metabolism
• Signal Transduction
• Tumor Suppressor Protein p53/metabolism

• Cell Line, Transformed
• Cell Line, Tumor
• Cyclin-Dependent Kinase Inhibitor p21/biosynthesis
• Cyclin-Dependent Kinase Inhibitor p21/genetics
• Genomic Instability
• Humans
• Liposarcoma, Myxoid/genetics
• Liposarcoma, Myxoid/metabolism
• Mutation
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism

P53 and its family members have been implicated in the direct regulation of the vitamin D receptor (VDR). Vitamin D- and p53-signaling pathways have a significant impact on spontaneous or carcinogen-induced malignant transformation of cells, with VDR and p53 representing important tumor suppressors. VDR and the p53/p63/p73 proteins all function typically as receptors or sensors that turn into transcriptional regulators upon stimulus, with the main difference being that the nuclear VDR is activated as a transcription factor after binding its naturally occurring ligand 1,25-dihydroxyvitamin D with high affinity while the p53 family of transcription factors, mostly in the nucleoplasm, responds to a large number of alterations in cell homeostasis commonly referred to as stress. An increasing body of evidence now convincingly demonstrates a cross-talk between vitamin D- and p53-signaling that occurs at different levels, has genome-wide implications and that should be of high importance for many malignancies, including non-melanoma skin cancer. One interaction involves the ability of p53 to increase skin pigmentation via POMC derivatives including alpha-MSH and ACTH. Pigmentation protects the skin against UV-induced DNA damage and skin carcinogenesis, yet on the other hand reduces cutaneous synthesis of vitamin D. A second level of interaction may be through the ability of 1,25-dihydroxyvitamin D to increase the survival of skin cells after UV irradiation. UV irradiation-surviving cells show significant reductions in thymine dimers in the presence of 1,25-dihydroxyvitamin D that are associated with increased nuclear p53 protein expression, and significantly reduced NO products. A third level of interaction is documented by the ability of vitamin D compounds to regulate the expression of the murine double minute 2 (MDM2) gene in dependence of the presence of wild-type p53. MDM2 has a well-established role as a key negative regulator of p53 activity. Finally, p53 and family members have been implicated in the direct regulation of VDR. This overview summarizes some of the implications of the cross-talk between vitamin D- and p53-signaling for carcinogenesis in the skin and other tissues.

• MDM2
• cancer
• p53
• vitamin D
• vitamin D receptor

• Chemotherapy
• Cisplatin
• Mutations
• NSCLC
• Randomized trial
• TP53

• Antineoplastic Agents/therapeutic use
• Carcinoma, Non-Small-Cell Lung/diagnosis
• Carcinoma, Non-Small-Cell Lung/genetics
• Chemotherapy, Adjuvant
• Cisplatin/therapeutic use
• Disease-Free Survival
• Humans
• Lung Neoplasms/diagnosis
• Lung Neoplasms/genetics
• Middle Aged
• Models, Molecular
• Mutation
• Prognosis
• Tumor Suppressor Protein p53/genetics

• 001 World Health Organization

The protein kinase C (PKC) family has been functionally linked to cancer. It has been suggested that atypical PKCs contribute to cell proliferation and cancer progression. With respect to breast cancer, PKCζ has been found to play a key role in intracellular transduction of mitogenic and apoptotic signals using mammary cell lines. However, little is known about its function in vivo. Here we examined the correlation between PKCζ protein levels and important clinicopathologic factors in breast cancer using patient samples. To conduct the study, 30 invasive ductal carcinoma cases and their paired normal tissues were used for tissue microarray analysis (TMA) and 16 were used for western blot analysis. In addition, the correlation between PKCζ expression levels and clinicopathologic characteristics was determined in 176 cases with relevant clinical data. Finally, the correlation between PKCζ and epithelial growth factor receptor 2 (HER2) expressions was determined using three breast cancer cell lines by western blot analysis. Both TMA and western blot results showed that PKCζ protein was highly expressed in primary tumors but not in paired normal tissue. The correlation study indicated that high PKCζ levels were associated with premenopausal patients (p = 0.019) and worse prognostic factors, such as advanced clinical stage, more lymph node involvement and larger tumor size. Both disease-free survival and overall survival rates were lower in the high PKCζ group than those in the low PKCζ group. No correlation was observed between PKCζ levels and age, histological grade, or estrogen or progesterone receptor expression status. A positive correlation between PKCζ and HER2 levels was observed in both tumor samples and cell lines. Our observations link PKCζ expression with factors pointing to worse prognosis, higher HER2 levels and a lower survival rate. This suggests that PKCζ protein levels may serve as a prognostic marker of breast cancer.

• Adult
• Breast Neoplasms/enzymology
• Breast Neoplasms/mortality
• Breast Neoplasms/pathology
• Carcinoma, Ductal, Breast/enzymology
• Carcinoma, Ductal, Breast/mortality
• Carcinoma, Ductal, Breast/secondary
• Cell Line, Tumor
• Disease-Free Survival
• Female
• Humans
• Isoenzymes/metabolism
• Kaplan-Meier Estimate
• Lymphatic Metastasis
• Middle Aged
• Protein Kinase C/metabolism
• Receptor, ErbB-2/metabolism

• breast cancer
• biomarkers
• american indian/alaska native

• Adenocarcinoma/ethnology
• Adenocarcinoma/genetics
• Adenocarcinoma/metabolism
• Adenocarcinoma/pathology
• Alaska
• Arizona
• Biomarkers, Tumor/analysis
• Biomarkers, Tumor/metabolism
• Breast Neoplasms/ethnology
• Breast Neoplasms/genetics
• Breast Neoplasms/metabolism
• Breast Neoplasms/pathology
• Female
• Humans
• Indians, North American
• Middle Aged