Delta-6-desaturase activity and arachidonic acid synthesis are increased in human breast cancer tissue

Abstract

Omega-6 (n-6) arachidonic acid (AA) and its pro-inflammatory metabolites, including prostaglandin E2 (PGE(2)), are known to promote tumorigenesis. Delta-6 desaturase (D6D) is the rate-limiting enzyme for converting n-6 linoleic acid (LA) to AA. Our objective was to determine if AA synthesis, specifically D6D activity, and PGE(2) levels are increased in cancerous breast tissue, and whether these variables differ between estrogen receptor positive (ER+) and negative (ER-) breast cancers. Gas chromatography was performed on surgical breast tissue samples collected from 69 women with breast cancer. Fifty-four had ER+ breast cancer, and 15 had ER- breast cancer. Liquid chromatography-mass spectrometry was used to determine PGE(2) levels. Lipid analysis revealed higher levels of LA metabolites (C18:3 n-6, C20:3 n-6, and AA) in cancerous tissue than in adjacent noncancerous tissue (P < 0.01). The ratio of LA metabolites to LA, a measure of D6D activity, was increased in cancerous tissue, suggesting greater conversion of LA to AA (P < 0.001), and was higher in ER- than in ER+ patients, indicating genotype-related trends. Similarly, PGE(2) levels were increased in cancerous tissue, particularly in ER- patients. The results showed that the endogenous AA synthetic pathway, D6D activity, and PGE(2) levels are increased in breast tumors, particularly those of the ER- genotype. These findings suggest that the AA synthetic pathway and the D6D enzyme in particular may be involved in the pathogenesis of breast cancer. The development of drugs and nutritional interventions to alter this pathway may provide new strategies for breast cancer prevention and treatment.

Figure 1

Fatty acid profile of the D6D pathway in tumor and non‐tumor breast tissue. Percentage of individual fatty acids of the delta‐6‐desaturase (D6D) pathway, including linoleic acid (LA, C18:2 n‐6), gamma‐linolenic acid (GLA, C18:3 n‐6), dihomo‐gamma‐linolenic acid (DGLA, C20:3 n‐6), and arachidonic acid (AA, C20:4 n‐6), as well as the sum of the metabolites that are downstream of LA (“LA Met.” = GLA + DGLA + AA). (n = 69 patients; *P < 0.05, **P < 0.003, ***P < 0.0001).

Figure 2

D6D activity in tumor and non‐tumor breast tissue. D6D activity is expressed as the ratio of the sum of linoleic acid (LA) metabolites to LA. The ratio is significantly higher in tumor tissue than in non‐tumor tissue. (n = 69 patients; ***P < 0.001).

Figure 3

Differential D6D activity in estrogen receptor positive (ER+) and negative (ER−) genotypes. D6D activity is significantly higher in tumor tissue than in non‐tumor tissue for both the ER+ and ER− genotypes, and the ratio is more profound in the ER− than ER+ genotype. (n = 15 for ER+ samples and n = 54 for ER− samples; **P < 0.01; ***P < 0.001).

Figure 4

PGE ₂ levels in tumor and non‐tumor breast tissue. Tumor samples had a significantly higher amount of prostaglandin E₂ (PGE ₂). (n = 16 for each group; **P < 0.01).

Figure 5

Differential PGE ₂ levels in estrogen receptor positive (ER+) and negative (ER−) genotypes. PGE ₂ levels are higher in the tumor tissue for each genotype, though this effect was only significant for the ER− genotype. (n = 8 for each group, **P < 0.01).