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

Dietary Oncopharmacognosy as a Crosswalk between Precision Oncology and Precision Nutrition

“…Precision onconutrition is the use of specific nutrients and dietary factors to enhance cancer treatment efficacy and to improve the prognosis for long-term survival. Precision onconutrition 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 [22].…”

“…Oncopharmacology is the developing and testing drugs and their interactions with cancer cells [22]. Analogously, pharmacognosy in oncology (which we term dietary oncopharmacognosy) identifies bioactive small molecules derived from dietary/food patterns, i.e., the collection of foods and beverages regularly consumed in a population, with cancer-relevant effects.…”

Lifestyle Modifications and Breast Cancer Risk

“…Collectively, the manuscripts in this Special Issue highlight the multiplicity of the cellular mechanisms by which diet and exercise may influence breast cancer risk. They include: (a) alterations in body composition resulting in changes in adipokine profile [12] and possibly hormone signaling [9]; (b) influence on cellular pathways and molecular targets such as PPAR7, mTOR, and lipogenesis, which affect the balance between cell proliferation and apoptosis [7]; (c) alterations in the long-term expression of cancer-associated genes, including p21, p53, and BRCA2 (5); and (d) epigenetic regulation [5,13]. In this regard, Gillman et al [13] assessed the methylation of 11 breast-cancer-related genes at baseline, after completing 16 weeks of supervised exercise intervention and six months after the completion of the intervention in a group of 135 women.…”