Long-chain fatty acid analogues suppress breast tumorigenesis and progression

Cancer Res. 2014 Dec 1;74(23):6991-7002. doi: 10.1158/0008-5472.CAN-14-0385. Epub 2014 Oct 10.

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.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Carcinogenesis / drug effects*
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Diet, Carbohydrate-Restricted / methods
  • Disease Progression
  • Fatty Acids / metabolism
  • Fatty Acids / pharmacology*
  • Female
  • Genes, src / genetics
  • Humans
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Lung Neoplasms / secondary
  • Male
  • Mice
  • Reactive Oxygen Species / metabolism
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects

Substances

  • Antineoplastic Agents
  • Fatty Acids
  • Reactive Oxygen Species
  • STAT3 Transcription Factor