http://cancer.med.unc.edu/nhayes/publications/Article%20PDFs/2010-03%20Cancer%20Cell.pdf

Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma.

https://www.cell.com/cancer-cell/pdf/S1535-6108(13)00183-9.pdf

SDH mutations establish a hypermethylator phenotype in paraganglioma.

Cancer chemoprevention is defined as the use of natural or synthetic agents that reverse, suppress or arrest carcinogenic and/or malignant phenotype progression towards invasive cancer. Phytochemicals obtained from vegetables, fruits, spices, herbs and medicinal plants, such as terpenoids, carotenoids, flavanoids, phenolic compounds, and other groups of compounds have shown promise in suppressing experimental carcinogenesis in various organs. Recent studies have indicated that mechanisms underlying chemopreventive action may include combinations of anti-oxidant, anti-inflammatory, immune-enhancing, and anti-hormone effects. Further, modification of drug-metabolizing enzymes, and influences on cell cycling and differentiation, induction of apoptosis, and suppression of proliferation and angiogenesis that play a role in the initiation and secondary modification of neoplastic development, have also been under investigation as possible mechanisms. This review will highlight the biological effects of terpenoids as chemopreventive agents on breast epithelial carcinogenesis, and the utility of intermediate biomarkers as indicators of premalignancy. Selected breast chemoprevention trials are discussed with a focus on strategies for trial design, and clinical outcomes. Future directions in the field of chemoprevention are proposed based on recently acquired mechanistic insights into breast carcinogenesis.

Terpenoids and breast cancer chemoprevention.

Cellular retinoid binding-proteins, CRBP, CRABP, FABP5: effects on retinoid metabolism, function and related diseases

Monoallelic point mutations of the NADP(+)-dependent isocitrate dehydrogenases IDH1 and IDH2 occur frequently in gliomas, acute myeloid leukemias, and chondromas, and display robust association with specific DNA hypermethylation signatures. Here we show that heterozygous expression of the IDH1(R132H) allele is sufficient to induce the genome-wide alterations in DNA methylation characteristic of these tumors. Using a gene-targeting approach, we knocked-in a single copy of the most frequently observed IDH1 mutation, R132H, into a human cancer cell line and profiled changes in DNA methylation at over 27,000 CpG dinucleotides relative to wild-type parental cells. We find that IDH1(R132H/WT) mutation induces widespread alterations in DNA methylation, including hypermethylation of 2010 and hypomethylation of 842 CpG loci. We demonstrate that many of these alterations are consistent with those observed in IDH1-mutant and G-CIMP+ primary gliomas and can segregate IDH wild-type and mutated tumors as well as those exhibiting the G-CIMP phenotype in unsupervised analysis of two primary glioma cohorts. Further, we show that the direction of IDH1(R132H/WT)-mediated DNA methylation change is largely dependent upon preexisting DNA methylation levels, resulting in depletion of moderately methylated loci. Additionally, whereas the levels of multiple histone H3 and H4 methylation modifications were globally increased, consistent with broad inhibition of histone demethylation, hypermethylation at H3K9 in particular accompanied locus-specific DNA hypermethylation at several genes down-regulated in IDH1(R132H/WT) knock-in cells. These data provide insight on epigenetic alterations induced by IDH1 mutations and support a causal role for IDH1(R132H/WT) mutants in driving epigenetic instability in human cancer cells.

/pdf/a-heterozygous-idh1r132h-wt-mutation-induces-genome-wide-pcpx35issq.pdf

A heterozygous IDH1R132H/WT mutation induces genome-wide alterations in DNA methylation

Background: Retinoic acid receptor (RAR) activation induces cell differentiation and may antagonize cancer progression. Cellular retinol-binding protein I (CRBP-I) functions in retinol storage and its expression is lower in human cancers than in normal cells. We hypothesized that retinol storage might be linked to RAR activation and thus that lowered CRBP-I function might impair RAR activity and cell differentiation. Methods: Sarcoma virus 40-immortalized human mammary epithelial cells (MTSV1-7) devoid of CRBP-I were transfected with wild-type CRBP-I or CRBP-I point mutants with low RA binding affinity. The subcellular localization of CRBP-I was investigated in these cells and in wild-type or CRBP-I null mouse mammary epithelial cells (MECs), using indirect immunofluorescence and sucrose gradient fractionation. RAR activity was assessed using reporter gene assays. Acinar differentiation and in vivo tumor growth were assessed in reconstituted basement membrane and athymic mice, respectively. Results: In cells expressing wild-type CRBP-I but not the CRBP-I mutants, CRBP-I was found mainly in lipid droplets, the retinol storage organelle, and this localization was associated with promotion of retinol storage by wild-type CRBP-I only. RAR activity was higher and acinar differentiation was observed in cells expressing wild-type but not mutant CRBP-I. RAR antagonist treatment blocked and chronic RA treatment mimicked, the CRBP-I induction of cell differentiation. Finally, CRBP-I suppressed tumorigenicity in athymic mice. Conclusions: Physiologic RAR activation is dependent on CRBP-Imediated retinol storage, and CRBP-I downregulation chronically compromises RAR activity, leading to loss of cell differentiation and tumor progression. [J Natl Cancer Inst 2005;97:21‐9]

Cellular Retinol-Binding Protein I, a Regulator of Breast Epithelial Retinoic Acid Receptor Activity, Cell Differentiation, and Tumorigenicity

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Cellular Retinol-Binding Protein I, a Regulator of Breast Epithelial Retinoic Acid Receptor Activity, Cell Differentiation, and Tumorigenicity