Fatty Acid Metabolites in Rapidly Proliferating Breast Cancer

Abstract

PurposeBreast cancers that over-express a lipoxygenase or cyclooxygenase are associated with poor survival possibly because they overproduce metabolites that alter the cancer’s malignant behaviors. However, these metabolites and behaviors have not been identified. We here identify which metabolites among those that stimulate breast cancer cell proliferation in vitro are associated with rapidly proliferating breast cancer.Experimental DesignWe used selective ion monitoring-mass spectrometry to quantify in the cancer and normal breast tissue of 27 patients metabolites that stimulate (15-, 12-, 5-hydroxy-, and 5-oxo-eicosatetraenoate, 13-hydroxy-octadecaenoate [HODE]) or inhibit (prostaglandin [PG]E2 and D2) breast cancer cell proliferation. We then related their levels to each cancer’s proliferation rate as defined by its Mib1 score.Results13-HODE was the only metabolite strongly, significantly, and positively associated with Mib1 scores. It was similarly associated with aggressive grade and a key component of grade, mitosis, and also trended to be associated with lymph node metastasis. PGE2 and PGD2 trended to be negatively associated with these markers. No other metabolite in cancer and no metabolite in normal tissue had this profile of associations.ConclusionsOur data fit a model wherein the overproduction of 13-HODE by 15-lipoxygenase-1 shortens breast cancer survival by stimulating its cells to proliferate and possibly metastasize; no other oxygenase-metabolite pathway, including cyclooxygenase-PGE2/D2 pathways, uses this specific mechanism to shorten survival.

Suppression of chemotherapy-induced cytokine/lipid mediator surge and ovarian cancer by a dual COX-2/sEH inhibitor

“…Our findings are consistent with reports that PGE 2 promotes lipid mediator class switching to stimulate resolution (48) and that it can act as a damageassociated molecular pattern in therapy-induced dead tumor cells to regulate inflammation (49). In addition, while 15-HETE and 11-HETE exhibit protumorigenic activity in breast cancer, these lipids have been shown to possess antitumorigenic activity in various cancers, including ovarian cancer (41,50). The COX-derived prostaglandins, LOX-derived HETEs, CYP450-derived DiHOMEs, and EpOMEs identified in the conditioned medium of the chemotherapy-generated tumor cell debris without macrophages indicate that the debris itself may be a source of tumor growthstimulation.…”

DHRS2 mediates cell growth inhibition induced by Trichothecin in nasopharyngeal carcinoma

“…In addition to glucose metabolism, lipid metabolism is also perturbed in rapidly proliferating cells [7][8][9]. Lipid metabolites play central roles in intermediary metabolism, in that they not only provide substrates for biological processes, but also impact on the control of cell cycle, proliferation and apoptosis [10][11][12][13][14][15]. Sphingosine-1-phosphate (S1P), a bioactive lipid, is reported to protect oral squamous cell carcinoma cells from cisplatin-induced death [16,17].…”

Metabolomics approach to assessing plasma 13- and 9-hydroxy-octadecadienoic acid and linoleic acid metabolite responses to 75-km cycling

“…Linoleic acid is the direct precursor to oxidized linoleic acid metabolites (OXLAMs) including 13-and 9-hydroxy-octadecadienoic acid (13-HODE ϩ 9-HODE) (9,15,29,33) (see http://www.genome.jp/kegg-bin/show_ pathway?map00591 for more detail). 13-HODE ϩ 9-HODE are stable oxidation products and have been linked to pathological conditions including atherosclerosis, diabetes, Alzheimer's disease, non-alcoholic steatohepatitis, psoriasis, chronic inflammation, obesity, and cancer (14,23,29,37). Plasma levels of 13-HODE ϩ 9-HODE are responsive to lifestyle interventions, with decreases reported when subjects adopt healthy diets and lose excess body weight (2,3,7,25).…”