American Association for Cancer Research
00085472can140385-sup-126840_3_supp_0_ncwk44.pdf (467.24 kB)

Supplemental Figures S1-S3 from Long-Chain Fatty Acid Analogues Suppress Breast Tumorigenesis and Progression

Download (467.24 kB)
journal contribution
posted on 2023-03-30, 22:48 authored by Udi Gluschnaider, Rachel Hertz, Sarit Ohayon, Elia Smeir, Martha Smets, Eli Pikarsky, Jacob Bar-Tana

Supplemental Figures S1-S3. c-Src/STAT3 crosstalk of Met-1 cells (S1); c-Src/STAT3 crosstalk of HCC1954 cells (S2); MEDICA amplifies radiation-suppressed clonogenity of HCC1954 cells (S3).



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. Cancer Res; 74(23); 6991–7002. ©2014 AACR.