miRNAs have emerged, in the last decade, as key players in the carcinogenic process, with many candidates identified as playing important roles in many aspects of tumor development, growth, metastasis, and drug resistance. More recently, polymorphisms in miRNAs themselves or in their binding sites in target genes have been identified to incur increased risk of breast cancer in certain populations. In addition, epigenetic regulation and differential expression of processing enzymes has been shown to contribute to the aberrant expression of miRNAs in breast cancer. This review focuses on the area of miRNA dysregulation in breast cancer through both genetic and epigenetic mechanisms, and the impact of this dysregulation on breast cancer risk and resistance to therapies.

https://cancerres.aacrjournals.org/content/canres/73/22/6554.full.pdf

miRNA dysregulation in breast cancer

Smoking prevalence for schizophrenic patients is higher than this for general population. More than 60% of schizophrenic patients are current smokers, which contributes to excessive mortality in these patients. The reasons for high frequency of both smoking prevalence and heavy smoking in schizophrenic patients is thought to be at least partially related to enhancement of brain dopaminergic activity, which, in turn, results in behavioral reinforcement due to stimulant effects. Smoking stimulates dopaminergic activity in the brain by inducing its release and inhibiting its degradation. There is also evidence that cigarette smoking can reduce deficits relative to dopamine hypofunction in prefrontal cortex. Recent neuroimaging studies have further contributed the evidence of complex influences of cigarette smoking on brain dopaminergic function. It has been suggested that smoking may be an attempt by schizophrenic patients to alleviate cognitive deficits and to reduce extrapyramidal side-effects induced by antipsychotic medication. Cigarette smoke also increases the activity of CYP 1A2 enzymes, thus decreasing the concentration of many drugs, including clozapine and olanzapine. There is also evidence that smoking is associated with increased clearance of tiotixene, fluphenazine and haloperidol. Given the high frequency of smoking in schizophrenic patients, clinicians need to check smoking status in each patient. Schizophrenic patients who smoke may require higher dosages of antipsychotics than nonsmokers. Conversely, upon smoking cessation, smokers may require a reduction in the dosage of antipsychotics.

/pdf/smoking-and-schizophrenia-51gb4a6fui.pdf

Smoking and schizophrenia.

Breast cancer risk and common single nucleotide polymorphisms in homologous recombination DNA repair pathway genes XRCC2, XRCC3, NBS1 and RAD51.

X-ray repair cross-complementing group 1 (XRCC1) plays an important role in base excision and single-strand break repair, as a scaffold protein that brings together proteins of the DNA repair complex, and appears to be a candidate for cancer risk. However, studies on the association between polymorphisms in this protein and cancer have yielded conflicting results. We performed a meta-analysis to investigate the association between the breast cancer and the XRCC1 polymorphisms Arg194Trp (9411 cases and 9783 controls), Arg399Gln (22 481 cases and 23 905 controls) and Arg280His (6062 cases and 5864 controls) in different inheritance models. Our analysis suggested that Arg399Gln was associated with a trend of increased breast cancer risk when using both dominant [odds ratio (OR) = 1.06, 95% confidence interval (CI): 1.00-1.13] and recessive models (OR = 1.12, 95% CI: 1.02-1.23) to analyse the data. In ethnic subgroups and using recessive model analysis: Arg399Gln increased breast cancer risk in Asians (OR = 1.26, 95% CI: 0.96-1.64) and Africans (OR = 1.80, 95% CI: 0.97-3.32), and also while only slightly increasing the breast cancer risk in Caucasians (OR = 1.08, 95% CI: 0.95-1.22). However, Arg194Trp (recessive model, OR = 0.95, 95% CI: 0.75-1.20) and Arg280His (recessive model, OR = 1.28, 95% CI: 0.64-2.55) did not appear to be risk factors for breast cancer. Larger scale primary studies are required to further evaluate the interaction of XRCC1 polymorphisms and breast cancer risk in specific populations.

XRCC1 Arg399Gln, Arg194Trp and Arg280His polymorphisms in breast cancer risk: a meta-analysis.

The human catechol-O-methyl transferase (COMT) gene contains multiple single-nucleotide polymorphisms, some of which are postulated to have clinical significance. This article reviews human studies that have explored the association between COMT polymorphisms and addiction to drugs, alcohol or tobacco. Most studies concentrate on the Val108/158Met polymorphism. Although there are reports indicating a positive association with COMT polymorphisms and addiction, the majority of the studies failed to detect such a link between them with one exception, smoking. It is unlikely that there would be any single gene that could be designated as 'the addiction gene'. Rather, there seems to be a great number of genes that are associated with addiction, among which COMT seems to have a minor role. Environmental factors and genetic milieu have a great impact on whether the small effects of COMT polymorphisms on risk of addiction can be detected in a given population. Sex differences complicate the gene-environment interplay even further.

Are genetic variants of COMT associated with addiction

Benign breast disease (BBD) is a risk factor for breast cancer and may have a heritable component. Deficient DNA repair has been implicated in breast cancer etiology and may exert its effect before BBD, a known precursor. The association between allelic variants in DNA repair genes and BBD was examined in a cohort of women in Washington County, Maryland. BBD was defined by two criteria: ( a ) a physician diagnosis of BBD or fibrocystic disease and/or ( b ) a benign breast biopsy. 3,212 women without BBD at baseline were genotyped for 12 candidate single nucleotide polymorphisms in seven DNA repair genes. Of these women, 482 subsequently reported a diagnosis of BBD. The Cox model was used to calculate hazard ratios (HR). Variant alleles of XRCC1 Arg194Trp (rs1799782) and ERCC4 Arg415Gln (rs1800067) were significantly associated with BBD [HR, 1.36; 95% confidence interval (95% CI), 1.06-1.74 and HR, 1.39; 95% CI, 1.09-1.76, respectively]. Similar estimates were also observed for each of the BBD criterion used. The BBD association for ERCC4 was even stronger among women with a family history of breast cancer (HR, 2.68; 95% CI, 1.52-4.66; P interaction = 0.02). This study suggests that variant alleles in DNA repair genes may modify BBD risk, a potential intermediate marker of breast cancer risk, particularly among high-risk subgroups. (Cancer Epidemiol Biomarkers Prev 2009;18(1):346–50)

https://cebp.aacrjournals.org/content/cebp/18/1/346.full.pdf

DNA Repair Gene Variants Associated with Benign Breast Disease in High Cancer Risk Women

A community-based study of cigarette smoking behavior in relation to variation in three genes involved in dopamine metabolism: Catechol-O-methyltransferase (COMT), dopamine beta-hydroxylase (DBH) and monoamine oxidase-A (MAO-A).

Judy Hoffman Bolton

Papers

DNA Repair Gene Variants Associated with Benign Breast Disease in High Cancer Risk Women

A community-based study of cigarette smoking behavior in relation to variation in three genes involved in dopamine metabolism: Catechol-O-methyltransferase (COMT), dopamine beta-hydroxylase (DBH) and monoamine oxidase-A (MAO-A).