Mammary tumour development is dose-dependently inhibited by n-3 polyunsaturated fatty acids in the MMTV-neu(ndl)-YD5 transgenic mouse model

Abstract

BackgroundBreast cancer is attributable to modifiable risk factors including the intake of dietary n-3 polyunsaturated fatty acids (PUFA). A key piece of evidence, yet to be addressed, that would demonstrate a causal relationship between n-3 PUFA and breast cancer, is a dose-dependent effect of n-3 PUFA on tumour outcomes. Thus, the objective of the present study was to determine whether n-3 PUFA reduces mammary gland tumor outcomes in a dose-dependent manner in female MMTV-neu(ndl)-YD5 transgenic mice, an aggressive model of human breast cancer.MethodsHarems were provided one of three experimental diets comprised of 0, 3 or 9% (w/w) menhaden fish oil containing n-3 PUFA. Female offspring were weaned onto the same parental diet and maintained on their respective diet for 20 weeks. Tumour onset, size and multiplicity were measured throughout the study. Fatty acid composition of mammary gland and tumours were determined by gas–liquid chromatography.ResultsTumour size was significantly (p < 0.05) reduced in a dose-dependent manner. n-3 PUFA were also incorporated in a dose-dependent manner; differential incorporation was observed for eicosapentaenoic and docosapentaenoic acids into mammary gland tissue, while docosahexaenoic acid was preferentially incorporated into tumours.ConclusionOverall, the present study provides fundamental knowledge about the dose-dependent effect of n-3 PUFA on tumour outcomes in a pre-clinical model and also sheds light on the differential role of individual n-3 PUFA on tumour outcomes.

The Role of n-3 Polyunsaturated Fatty Acids in the Prevention and Treatment of Breast Cancer

“…Thus, this study provided a direct evidence for a protective effect of n -3 PUFA via both complementary genetic and conventional dietary approaches [ 116 ]. In order to understand the dose-dependent effect of n -3 PUFA on mammary gland tumor development, Leslie et al further demonstrated a dose-response relationship of 0%, 3% and 9% (w/w) menhaden oil on tumor burden reduction in MMTV-neu-YD5 mice [ 21 ]. In line with the previous study, the observed dose-dependent effects of n -3 PUFA were associated with a dose-dependent change in the fatty acid profile, reflecting a decreased n -6/ n -3 ratio in the mammary glands and an increased of EPA and DHA in tumor phospholipid classes [ 21 ].…”

“…In order to understand the dose-dependent effect of n -3 PUFA on mammary gland tumor development, Leslie et al further demonstrated a dose-response relationship of 0%, 3% and 9% (w/w) menhaden oil on tumor burden reduction in MMTV-neu-YD5 mice [ 21 ]. In line with the previous study, the observed dose-dependent effects of n -3 PUFA were associated with a dose-dependent change in the fatty acid profile, reflecting a decreased n -6/ n -3 ratio in the mammary glands and an increased of EPA and DHA in tumor phospholipid classes [ 21 ]. This is consistent with an earlier human clinical trial which showed dietary DHA and EPA supplementation caused a dose-dependent increase of n -3 PUFA in serum and breast adipose tissues of BC patients [ 118 ].…”

“…Results from both in vivo and in vitro studies suggest that n -6 PUFA accelerate tumorigenesis, in contrast, n -3 PUFA may have anticancer effects [ 18 , 19 , 20 , 21 , 22 ]. Western diets are typically deficient in n -3 PUFA and high in n -6 PUFA compared with traditional Asian diets [ 8 , 23 , 24 ].…”

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

“…There is increasing evidence to support the view that LC n -3 PUFA, specifically EPA and DHA, inhibit the growth of colorectal, breast and prostate cancer cell lines [ 27 , 40 , 41 , 42 ] and inhibit tumour growth in animal models [ 43 , 44 , 45 ]. Current evidence in humans is less clear and epidemiological data is largely inconsistent [ 9 , 27 , 28 ].…”

The Role of PPARγ Ligands in Breast Cancer: From Basic Research to Clinical Studies

“…Moreover, a novel synthetic PPARγ ligand, the triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), was found to lower the tumor growth of MDA-MB-435 breast cancer cells implanted in nude mice [ 130 ]. Suppression of tumor cell growth by ω-3 PUFAs has been confirmed in vivo using cancer animal models mainly represented by xenograft nude mice implanted with different tumor cell types [ 131 , 132 , 133 , 134 , 135 ] and by transgenic rodent models [ 136 , 137 , 138 ]. Indeed, dietary supplementation with ω-3 PUFAs has been reported to increase PPARγ protein expression, which was concomitant with a reduction of tumor burden in rats with induced mammary carcinogenesis [ 139 ].…”