Association of a functional polymorphism (Gln261Arg) in 12-lipoxygenase with breast cancer

Abstract

Abstract. the overexpression of arachidonyl lipoxygenase-12 (alOx12) in breast cancer has been reported. hence, we examined whether a non-synonymous polymorphism of alOx12 (mrna, a835G; Gln261arg) is associated with breast cancer in females. the polymorphism was detected in genomic dna by pcr-rFlp. the association between the a835G polymorphism and breast cancer risk was measured by odds ratio (OR) with 95% confidence intervals (CIs) using Fisher's exact test, and differences were considered significant at p<0.05. the frequencies of aa (wild-type), GG (homozygous variant) and aG (heterozygous variant) were 59.5, 0.9 and 39.6% in the controls, and 39.3, 2.5 and 58.2% in the breast cancer cases, respectively. the frequency of the aG genotype was higher in the patients compared to the controls (p<0.0014). the frequency of the GG variant was 2.5 and 0.9% in the cancer subjects and controls, respectively. the relative risk of breast cancer was 2 times greater (Or=2.227) at 95% ci when compared to the relative risk of the heterozygous variant. For the GG genotype, the risk was 4 times greater (Or=4.125) at 95% ci than that of the controls, suggesting a positive association of the aG genotype with the occurrence of breast cancer. the frequencies of the polymorphism were different in different populations. the arg/Gln and arg/arg variants were associated with an increased risk of breast cancer, and the frequencies of the variants differed considerably among various populations. The identification of a gene with links to breast cancer may impact screening, diagnosis and drug development.

A Sucrose-Enriched Diet Promotes Tumorigenesis in Mammary Gland in Part through the 12-Lipoxygenase Pathway

“…Higher levels of 12-LOX were also observed in tumors from patients who died of breast cancer (30). Furthermore, a non-synonymous polymorphism of A12LOX (mRNA, A535G; gln261Arg) has been associated with increased risk of breast cancer, especially the Arg/Gln and Arg/Arg variants (31). In line with this, a recent preclinical study further documented that 12-HETE serves as a key mediator of tumor cell invasion into lymphatic vessels and formation of lymph node metastasis in ductal mammary carcinomas (32).…”

The role of lipoxygenases in pathophysiology; new insights and future perspectives

“…The best-studied example includes mutation of E261R (835A>G), which causes an increase in 12-LOX activity, with a potential link to esophageal squamous cell carcinoma [64] . This mutation has also been associated with colorectal cancer [47,65] and breast cancer [48] . An in vitro and in vivo study has shown that 12-LOX plays a role in the proliferation and antiapoptosis of hepatocellular cells, suggesting that this carcinogenic function of ALOX12 requires endogenously generated lipid mediators [66] .…”

“…These enzymes are expressed in leukocytes in humans and in platelets, megakaryocytes, and skin in mice [45,46] . Genetic studies have suggested that ALOX12 gene polymorphisms are associated with cancers [47,48] , neurological disorders [49,50] , hypertension [51,52] , fat mass [53] , and bone mineral density [54–57] . The mechanism of regulation of 12-LOX expression has been studied in several models.…”

Cancer Risk and Eicosanoid Production: Interaction between the Protective Effect of Long Chain Omega-3 Polyunsaturated Fatty Acid Intake and Genotype

“…A recent meta-analysis found that polymorphisms in the ALOX12 gene at the Gln261Arg locus may influence cancer risk in Asian populations but not in Caucasians [ 60 ]. Furthermore, carriers of the variant in homozygous or heterozygous form had an increased risk for breast cancer, also demonstrating differences across ethnic populations [ 61 ]. The same polymorphism also showed an association with risk of colorectal adenomas [ 62 ].…”

“…Limitations in these studies include recall bias in the FFQ and diet diaries, which are commonly used in large studies such as cohorts or case-control designs due to lack of affordable and better alternatives. Furthermore, ethnicity must be adjusted for in studies, as ethnicity may influence the relationship between dietary n -3 PUFA, cancer risk and genotype, as highlighted earlier [ 60 , 61 ]. Additional factors potentially influencing the outcome of the studies reviewed herein, include the stage of the disease, as LC n -3 PUFA may interact differently with genotypes as the physiology of the tumour changes, and fish contaminants.…”