Building a Foundation for Precision Onco-Nutrition: Docosahexaenoic Acid and Breast Cancer

SIMPLE SUMMARY: Precision onco-nutrition (PON) is the use of specific nutrients and dietary factors to enhance cancer treatment efficacy and to improve the prognosis for long-term survival. PON requires integration of an understanding of nutrient metabolism with knowledge of the signaling pathways characteristic of each molecular subtype of cancer which can be targeted to improve treatment and control efficacies. Herein we report differences among n-3 fatty acids on the growth and survival of established breast cancer cell lines. Docosahexaenoic acid (DHA) is shown to have greater anticancer activity than eicosapentaenoic acid (EPA). Moreover, we show that a penultimate metabolite of one pathway by which DHA is metabolized inhibited the growth of common molecular subtypes of breast cancer via differential effects on identified canonical signaling pathways and the functions within the cell that they regulate. These findings provide a knowledge base for juxtaposing molecular subtype targeted treatment strategies with the adjuvant use of specific n-3 fatty acid metabolites as an example of precision onco-nutrition for the management and control of breast cancer. ABSTRACT: In vivo evidence of heterogeneous effects of n-3 fatty acids (N3FA) on cell signaling pathways associated with the reduced growth of breast cancer has been reported and is consistent with the expectation that N3FA will not exert uniform effects on all molecular subtypes of the disease. Similarly, available evidence indicates that many metabolites of N3FA are synthesized by mammalian cells and that they exert metabolite-specific biological activities. To begin to unravel the complex relationships among molecular subtypes and effects exerted by specific N3FA metabolites on those pathways, proof-of-concept experiments were conducted using cell lines representative of common molecular subtypes of human breast cancer. N3FA differed in anticancer activity with docosahexaenoic acid (DHA) having greater anticancer activity than eicosapentaenoic acid. 4-oxo-docosahexaenoic (4-oxo-DHA), a penultimate metabolite of 5-lipoxygenase mediated DHA metabolism, induced dose-dependent inhibition of cell number accumulation with apoptosis as a primary effector mechanism. Interrogation of protein expression data using the Ingenuity Pathway Analysis (IPA) bioinformatics platform indicated that 4-oxo-DHA differentially impacted six canonical pathways and the cellular functions they regulate across common molecular subtypes of breast cancer. This included the endocannabinoid pathway for cancer inhibition that has not been previously reported. These findings provide a rationale for juxtaposing molecular subtype targeted treatment strategies with the adjuvant use of specific N3FA metabolites as an example of precision onco-nutrition (PON) for the management and control of breast cancer.