Fatty acid desaturase activity and single nucleotide polymorphism of fatty acid desaturase gene and breast cancer risk in estrogen receptor subtype.

Abstract

e12551 Background: Breast cancer (BC) is the most common cancer in women. Various mechanisms are known to promote tumourogenesis. Arachidonic acid and its metabolites are one such pathway which promote tumorigenesis by inflammation and angiogenesis. It can be hypothesized that fatty acid metabolism is dysregulated in women with BC. We compared the fatty acid desaturases activity in women with BC and the control women. Breast cancer, which is a diet-related inflammatory disease, is also associated with the plasma concentration of omega fatty acids (n-3 and n-6), and can have an impact of its genetic variants. We studied the association between genetic variant rs174537 of fatty acid desaturase gene 1(FADS 1) and the estrogen receptor positive BC. Methods: Sixty women diagnosed with BC and 40 control women without BC between the age group of 25-60years of age were recruited for comparing the fatty acid desaturases activity. The tumors were classified by Estrogen Receptor (ER) status. Fatty acid Desaturases activities (D5, D6 and D9) were estimated as the ratio of product to precursor of individual fatty acids in plasma lipids. To study the association between genetic variant rs174537 of fatty acid desaturase gene 1(FADS 1) and the estrogen receptor positive BC, we recruited 102 (ER +ve, n = 53; ER -ve,n = 49) women with proven BC, prior to therapy. SNP rs 174537(G > T) showed maximum variability and the strongest genetic determinant in the Genome-wide association study were genotyped using Sanger sequencing. Results: Decreased levels of delta 5 and delta 9 desaturases activity and increased delta 6 desaturase activity were associated with the adverse profile of BC than the control group. Estrogen Receptor status also showed variation in desaturase activity. The highest tertile of Alphalinolenic acid (ALA) showed a significantly reduced association with BC compared to the lowest tertile (OR = 0.2, 95 %CL = 0.1–1.14, P = 0.03). Median values of ALA were higher in GT/TT genotype in ER +ve molecular subtype (P = 0.03) and Docosapentaenoic acid (DPA) was higher in GG genotype of ER -ve molecular subtype (P = 0.037). When both the groups were put together the highest tertile of GG tertile showed significantly reduced association with BC compared with the other lowest tertiles of GG and GT/TT genotypes (OR, 95% CL = 0.45(0.2–0.9). Conclusions: We conclude that unbalanced polyunsaturated fatty acids and impaired fatty acid desaturation plays a role in the pathogenesis of BC. The high levels of arachidonic acid and low levels of n-3 fatty acids result in a pro-inflammatory milieu which might contribute to the pathogenesis of BC. We also conclude that the individuals with genetically determined lower activity of FADS1 (minor allele T) will derive greater advantage from n-3 fatty acids than those with higher FADS1 activity (G allele).