Long-chain fatty acid analogues suppress breast tumorigenesis and progression

Udi Gluschnaider, Rachel Hertz, Sarit Ohayon, Elia Smeir, Martha Smets, Eli Pikarsky, Jacob Bar-Tana*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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 ef fi cacy of nonesteri fi ed 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 esteri fi ed 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 con firmed that tumor growth could be suppressed by a carbohydraterestricted 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 fi ndings suggest that MEDICA analogues may offer therapeutic potential in breast cancer and overcome the poor compliance of patients to dietary carbohydrate restriction.

Original languageAmerican English
Pages (from-to)6991-7002
Number of pages12
JournalCancer Research
Volume74
Issue number23
DOIs
StatePublished - 1 Dec 2014

Bibliographical note

Publisher Copyright:
©2014 American Association for Cancer Research.

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