title: Long-chain fatty acid analogues suppress breast tumorigenesis and progression.
abstract: Obesity and type 2 diabetes (T2D) are associated with increased breast cancer incidence and mortality, whereas carbohydrate-restricted ketogenic diets ameliorate T2D and suppress breast cancer. These observations suggest an inherent efficacy of nonesterified long-chain fatty acids (LCFA) in suppressing T2D and breast tumorigenesis. In this study, we investigated novel antidiabetic MEDICA analogues consisting of methyl-substituted LCFA that are neither β-oxidized nor esterified to generate lipids, prompting interest in their potential efficacy as antitumor agents in the context of breast cancer. In the MMTV-PyMT oncomouse model of breast cancer, in which we confirmed that tumor growth could be suppressed by a carbohydrate-restricted ketogenic diet, MEDICA treatment suppressed tumor growth, and lung metastasis, promoting a differentiated phenotype while suppressing mesenchymal markers. In human breast cancer cells, MEDICA treatment attenuated signaling through the STAT3 and c-Src transduction pathways. Mechanistic investigations suggested that MEDICA suppressed c-Src-transforming activity by elevating reactive oxygen species production, resulting in c-Src oxidation and oligomerization. Our findings suggest that MEDICA analogues may offer therapeutic potential in breast cancer and overcome the poor compliance of patients to dietary carbohydrate restriction.
authors.affiliation: Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel.
authors.forename: Udi
authors.initials: U
authors.lastname: Gluschnaider
authors.affiliation: Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Hertz
authors.affiliation: Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel.
authors.forename: Sarit
authors.initials: S
authors.lastname: Ohayon
authors.affiliation: Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel.
authors.forename: Elia
authors.initials: E
authors.lastname: Smeir
authors.affiliation: Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel.
authors.forename: Martha
authors.initials: M
authors.lastname: Smets
authors.affiliation: Department of Pathology, Hebrew University Medical School, Jerusalem, Israel.
authors.forename: Eli
authors.initials: E
authors.lastname: Pikarsky
authors.affiliation: Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel. jacobb@ekmd.huji.ac.il.
authors.forename: Jacob
authors.initials: J
authors.lastname: Bar-Tana
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D063646:Carcinogenesis / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D050528:Diet, Carbohydrate-Restricted / Q000379:methods; D018450:Disease Progression; D005227:Fatty Acids / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D016391:Genes, src / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D008297:Male; D051379:Mice; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D005227:Fatty Acids; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor