Long chain fatty acid analogs suppress breast tumorigenesis and progression

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 anti-diabetic MEDICA analogs consisting of methyl-substituted LCFA that are neither β-oxidized nor esterified to generate lipids, prompting interest in their potential efficacy as anti-tumor agents in the context of breast cancer. In the MMTV-PyMT oncomouse model of breast cancer, where 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 ROS production, resulting in c-Src oxidation and oligomerization. Our findings suggest that MEDICA analogs may offer therapeutic potential in breast cancer and overcome the poor compliance of patients to dietary carbohydrate restriction.