Single nucleotide polymorphism of fatty acid desaturase gene and breast cancer risk in estrogen receptor subtype

Preethika, A; Sonkusare, Shipra; Kumari, N. Suchetha

doi:10.1016/j.gene.2022.146330

Cited by 6 publications

(9 citation statements)

References 32 publications

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“…These eQTLs are in strong linkage disequilibrium and studies showed that these SNPs can predict FADS1 expression as well as FADS1 activity that is reflected in circulating PUFA levels in humans ( 19 , 58 , 59 ). Change in the level of PUFAs that are due to these genetic variants, are demonstrated to be associated with cancer risk ( 31 , 33 , 60 , 61 ). Thus, it is possible that SNP genotyping may be a pre-screening strategy for identifying most suitable patients for such a therapy.…”

Section: Discussionmentioning

confidence: 99%

Fatty acid desaturase 1 (FADS1) is a cancer marker for patient survival and a potential novel target for precision cancer treatment

et al. 2022

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Fatty Acid Desaturase-1 (FADS1) or delta 5 desaturase (D5D) is a rate-limiting enzyme involved in the biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFAs), i.e., arachidonic acid (ARA) and eicosapentaenoic (EPA). These LC-PUFAs and their metabolites play essential and broad roles in cancer cell proliferation, metastasis, and tumor microenvironment. However, the role of FADS1 in cancers remains incompletely understood. Utilizing The Cancer Genome Atlas (TCGA) database, we explored the role of FADS1 across different cancer types using multiple bioinformatics and statistical tools. Moreover, we studied the impact of a FADS1 inhibitor (D5D-IN-326) on proliferation of multiple cancer cell lines. We identified that FADS1 gene is a predictor for cancer survival in multiple cancer types. Compared to normal tissue, the mRNA expression of FADS1 is significantly increased in primary tumors while even higher in metastatic and recurrent tumors. Mechanistically, pathway analysis demonstrated that FADS1 is associated with cholesterol biosynthesis and cell cycle control genes. Interestingly, FADS1 expression is higher when TP53 is mutated. Tumors with increased FADS1 expression also demonstrated an increased signatures of fibroblasts and macrophages infiltration among most cancer types. Our in vitro assays showed that D5D-IN-326 significantly inhibited cell proliferation of kidney, colon, breast, and lung cancer cell lines in a dose-dependent manner. Lastly, single nucleotide polymorphisms (SNPs) which are well-established expression quantitative trait loci (eQTLs) for FADS1 in normal human tissues are also significantly correlated with FADS1 expression in tumors of multiple tissue types, potentially serving as a marker to stratify cancer patients with high/low FADS1 expression in their tumor tissue. Our study suggests that FADS1 plays multiple roles in cancer biology and is potentially a novel target for precision cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Fatty acid desaturase 1 (FADS1) is a cancer marker for patient survival and a potential novel target for precision cancer treatment

et al. 2022

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“…A more generalized downregulation of desaturase enzymes is observed in metformin-treated cells, with significant reductions both in activity and expression of FADS1-3 [ 49 ]. Metformin specifically reduces FADS1 activity [ 46 ] and individuals with FADS1 genetic variants with reduced activity have decreased breast cancer risk [ 50 ]. Less FADS1 and 2 activity leads to a reduction in long chain omega-6 fatty acids and a less pro-inflammatory tissue milieu that may aid in reducing cancer risk and growth promotion [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

Metabolomic profiles of metformin in breast cancer survivors: a pooled analysis of plasmas from two randomized placebo-controlled trials

et al. 2022

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Background Obesity is a major health concern for breast cancer survivors, being associated with high recurrence and reduced efficacy during cancer treatment. Metformin treatment is associated with reduced breast cancer incidence, recurrence and mortality. To better understand the underlying mechanisms through which metformin may reduce recurrence, we aimed to conduct metabolic profiling of overweight/obese breast cancer survivors before and after metformin treatment. Methods Fasting plasma samples from 373 overweight or obese breast cancer survivors randomly assigned to metformin (n = 194) or placebo (n = 179) administration were collected at baseline, after 6 months (Reach For Health trial), and after 12 months (MetBreCS trial). Archival samples were concurrently analyzed using three complementary methods: untargeted LC–QTOF-MS metabolomics, targeted LC–MS metabolomics (AbsoluteIDQ p180, Biocrates), and gas chromatography phospholipid fatty acid assay. Multivariable linear regression models and family-wise error correction were used to identify metabolites that significantly changed after metformin treatment. Results Participants (n = 352) with both baseline and study end point samples available were included in the analysis. After adjusting for confounders such as study center, age, body mass index and false discovery rate, we found that metformin treatment was significantly associated with decreased levels of citrulline, arginine, tyrosine, caffeine, paraxanthine, and theophylline, and increased levels of leucine, isoleucine, proline, 3-methyl-2-oxovalerate, 4-methyl-2-oxovalerate, alanine and indoxyl-sulphate. Long-chain unsaturated phosphatidylcholines (PC ae C36:4, PC ae C38:5, PC ae C36:5 and PC ae C38:6) were significantly decreased with the metformin treatment, as were phospholipid-derived long-chain n-6 fatty acids. The metabolomic profiles of metformin treatment suggest change in specific biochemical pathways known to impair cancer cell growth including activation of CYP1A2, alterations in fatty acid desaturase activity, and altered metabolism of specific amino acids, including impaired branched chain amino acid catabolism. Conclusions Our results in overweight breast cancer survivors identify new metabolic effects of metformin treatment that may mechanistically contribute to reduced risk of recurrence in this population and reduced obesity-related cancer risk reported in observational studies. Trial registration ClinicalTrials.gov identifier: NCT01302379 and EudraCT Protocol #: 2015-001001-14.

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“…More importantly, DHA may also reduce the invasive potential of certain cancers, which is one of the main complications with advanced cancers. It should be noted that some genetic determinant, i.e., single nucleotide polymorphism rs174537, may lead to an increased benefit of an n-3 LC-PUFA diet by lowering FADS1 [88]. In addition, and beyond breast cancer, it has been shown that n-3 LC-PUFAs may decrease cancer risk by affecting genetic variants of inflammatory pathways, oxidative stress, and tumor apoptosis [118].…”

Section: Discussion and Perspectivesmentioning

confidence: 99%

“…In addition, and beyond breast cancer, it has been shown that n-3 LC-PUFAs may decrease cancer risk by affecting genetic variants of inflammatory pathways, oxidative stress, and tumor apoptosis [118]. This suggests the importance of (nutri-)genomics studies to identify genetic variants, and to increase the efficiency of n-3 LC-PUFA diet preventive action on breast cancer by a targeted or personalized therapeutic regimen to circumvent individual variation [88,118].…”

Section: Discussion and Perspectivesmentioning

confidence: 99%

“…However, the synthesis of SPMs in humans is not clearly linked to n-3 LC-PUFA dietary supplementation [87]. As noted by Preethika et al in an observational study of 102 breast cancer patients, high levels of ARA and low levels of n-3 LC-PUFAs resulted in a pro-inflammatory environment, which might contribute to breast cancer [88]. In addition, individuals with genetically determined lower fatty acid desaturase 1 (FADS1) activity due to the presence of the minor T allele will derive more benefit from n-3 LC-PUFAs, including a reduced risk of breast cancer, than those with higher FADS1 activity (G allele) [88].…”

Section: Anti-inflammatory Effect Of N-3 Lc-pufas and Cancer Preventionmentioning

confidence: 99%

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Contribution of n-3 Long-Chain Polyunsaturated Fatty Acids to the Prevention of Breast Cancer Risk Factors

Fodil

Blanckaert

Ulmann

et al. 2022

IJERPH

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Nowadays, diet and breast cancer are studied at different levels, particularly in tumor prevention and progression. Thus, the molecular mechanisms leading to better knowledge are deciphered with a higher precision. Among the molecules implicated in a preventive and anti-progressive way, n-3 long chain polyunsaturated fatty acids (n-3 LC-PUFAs) are good candidates. These molecules, like docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids, are generally found in marine material, such as fat fishes or microalgae. EPA and DHA act as anti-proliferative, anti-invasive, and anti-angiogenic molecules in breast cancer cell lines, as well as in in vivo studies. A better characterization of the cellular and molecular pathways involving the action of these fatty acids is essential to have a realistic image of the therapeutic avenues envisaged behind their use. This need is reinforced by the increase in the number of clinical trials involving more and more n-3 LC-PUFAs, and this, in various pathologies ranging from obesity to a multitude of cancers. The objective of this review is, therefore, to highlight the new elements showing the preventive and beneficial effects of n-3 LC-PUFAs against the development and progression of breast cancer.

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Single nucleotide polymorphism of fatty acid desaturase gene and breast cancer risk in estrogen receptor subtype

Cited by 6 publications

References 32 publications

Fatty acid desaturase 1 (FADS1) is a cancer marker for patient survival and a potential novel target for precision cancer treatment

Fatty acid desaturase 1 (FADS1) is a cancer marker for patient survival and a potential novel target for precision cancer treatment

Metabolomic profiles of metformin in breast cancer survivors: a pooled analysis of plasmas from two randomized placebo-controlled trials

Contribution of n-3 Long-Chain Polyunsaturated Fatty Acids to the Prevention of Breast Cancer Risk Factors

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