Polymorphisms of Phase I and Phase II Enzymes and Breast Cancer Risk

Justenhoven, Christina

doi:10.3389/fgene.2012.00258

Cited by 12 publications

(6 citation statements)

References 77 publications

(87 reference statements)

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“…Genetic variations in such gene regions require an adapted primer design and amplification conditions which allow specific genotyping of the loci of interest (Justenhoven et al, 2010; The MARIE-GENICA Consortium, 2010). Therefore, polymorphic loci in homologous sequences are usually exempted from GWAS arrays, and can be analyzed in specially designed low-plex genotyping assays or small scale microarrays, e.g., the AmpliChip® CYP450 Test (Roche Diagnostic GmbH, Germany), the DMET™ Plus Solution (Affymetrix Inc. CA, USA) or the VeraCode® ADME Core Panel (Illumina, Inc. CA, USA) (Justenhoven, 2012). Sequence similarities are rather common among genes coding for phase I and II enzymes as well as transporters, for example P450 cytochrome 3A (CYP3A) genes with more than 70% homology (Filipits et al, 1999; Domanski et al, 2001), the UDP glucuronosyl transferases 1 (UGT1) genes with more than 50% homology (Gong et al, 2001) and the solute carrier organic anion transporter (SLCO) genes with more than 40% homology (Hagenbuch and Meier, 2004).…”

Section: Introductionsmentioning

confidence: 99%

The UGT1A6_19_GG genotype is a breast cancer risk factor

Justenhoven¹,

Obazee²,

Winter³

et al. 2013

Front. Genet.

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Validation of an association between the UGT1A6_19_T>G (rs6759892) polymorphism and overall breast cancer risk. A pilot study included two population-based case-control studies from Germany (MARIE-GENICA). An independent validation study comprised four independent breast cancer case-control studies from Finland (KBCP, OBCS), Germany (BBCC), and Sweden (SASBAC). The pooled analysis included 7418 cases and 8720 controls from all six studies. Participants were of European descent. Genotyping was done by MALDI-TOF MS and statistical analysis was performed by logistic regression adjusted for age and study. The increased overall breast cancer risk for women with the UGT1A6_19_GG genotype which was observed in the pilot study was confirmed in the set of four independent study collections (OR 1.13, 95% CI 1.05–1.22; p = 0.001). The pooled study showed a similar effect (OR 1.09, 95% CI 1.04–1.14; p = 0.001). The risk effect on the basis of allele frequencies was highly significant, the pooled analysis showed an OR of 1.11 (95% CI 1.06–1.16; p = 5.8 × 10−6). We confirmed the association of UGT1A6_19_GG with increased overall breast cancer risk and conclude that our result from a well powered multi-stage study adds a novel candidate to the panel of validated breast cancer susceptibility loci.

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Section: Introductionsmentioning

confidence: 99%

The UGT1A6_19_GG genotype is a breast cancer risk factor

Justenhoven¹,

Obazee²,

Winter³

et al. 2013

Front. Genet.

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“…However, these studies typically employ sex-combined models and report results in a sex-combined fashion 14 , because of the sample size/power limitations, hence underestimating the role of sex as a modifier of the drug response. Moreover, functions of DMET genes are critical in determining the amount of endogenous substrates (e.g., serum biomarkers that are frequently used for disease diagnoses 15,16 ). A comprehensive study of sex differences in the genetic basis of DMET genes and their health impact is currently lacking.…”

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confidence: 99%

Deciphering genetic causes for sex differences in human health through drug metabolism and transporter genes

et al. 2023

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Sex differences have been widely observed in human health. However, little is known about the underlying mechanism behind these observed sex differences. We hypothesize that sex-differentiated genetic effects are contributors of these phenotypic differences. Focusing on a collection of drug metabolism enzymes and transporters (DMET) genes, we discover sex-differentiated genetic regulatory mechanisms between these genes and human complex traits. Here, we show that sex-differentiated genetic effects were present at genome-level and at DMET gene regions for many human complex traits. These sex-differentiated regulatory mechanisms are reflected in the levels of gene expression and endogenous serum biomarkers. Through Mendelian Randomization analysis, we identify putative sex-differentiated causal effects in each sex separately. Furthermore, we identify and validate sex differential gene expression of a subset of DMET genes in human liver samples. We observe higher protein abundance and enzyme activity of CYP1A2 in male-derived liver microsomes, which leads to higher level of an active metabolite formation of clozapine, a commonly prescribed antipsychotic drug. Taken together, our results demonstrate the presence of sex-differentiated genetic effects on DMET gene regulation, which manifest in various phenotypic traits including disease risks and drug responses.

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“…Phase 1 enzymes exert various effects beyond inducing pro-carcinogenic P450 enzymes. They also play a role in regulating DNA and histone methylation in enzymes like BRCA1 [ 171 ]. In addition, these enzymes can induce AhR activation promoting COX2 expression [ 172 ] ( Figure 7 ).…”

Section: Alternative Therapeutic Approaches For Preventing Nos2/cox2 ...mentioning

confidence: 99%

NOS2 and COX-2 Co-Expression Promotes Cancer Progression: A Potential Target for Developing Agents to Prevent or Treat Highly Aggressive Breast Cancer

Coutinho,

Femino,

Gonzalez

et al. 2024

IJMS

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Nitric oxide (NO) and reactive nitrogen species (RNS) exert profound biological impacts dictated by their chemistry. Understanding their spatial distribution is essential for deciphering their roles in diverse biological processes. This review establishes a framework for the chemical biology of NO and RNS, exploring their dynamic reactions within the context of cancer. Concentration-dependent signaling reveals distinctive processes in cancer, with three levels of NO influencing oncogenic properties. In this context, NO plays a crucial role in cancer cell proliferation, metastasis, chemotherapy resistance, and immune suppression. Increased NOS2 expression correlates with poor survival across different tumors, including breast cancer. Additionally, NOS2 can crosstalk with the proinflammatory enzyme cyclooxygenase-2 (COX-2) to promote cancer progression. NOS2 and COX-2 co-expression establishes a positive feed-forward loop, driving immunosuppression and metastasis in estrogen receptor-negative (ER-) breast cancer. Spatial evaluation of NOS2 and COX-2 reveals orthogonal expression, suggesting the unique roles of these niches in the tumor microenvironment (TME). NOS2 and COX2 niche formation requires IFN-γ and cytokine-releasing cells. These niches contribute to poor clinical outcomes, emphasizing their role in cancer progression. Strategies to target these markers include direct inhibition, involving pan-inhibitors and selective inhibitors, as well as indirect approaches targeting their induction or downstream effectors. Compounds from cruciferous vegetables are potential candidates for NOS2 and COX-2 inhibition offering therapeutic applications. Thus, understanding the chemical biology of NO and RNS, their spatial distribution, and their implications in cancer progression provides valuable insights for developing targeted therapies and preventive strategies.

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Polymorphisms of Phase I and Phase II Enzymes and Breast Cancer Risk

Cited by 12 publications

References 77 publications

The UGT1A6_19_GG genotype is a breast cancer risk factor

The UGT1A6_19_GG genotype is a breast cancer risk factor

Deciphering genetic causes for sex differences in human health through drug metabolism and transporter genes

NOS2 and COX-2 Co-Expression Promotes Cancer Progression: A Potential Target for Developing Agents to Prevent or Treat Highly Aggressive Breast Cancer

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