Cancer cells alter the metabolism in their microenvironment to sustain their survival, growth and progression. Heat is an essential factor that can affect metabolism. However, it is unclear whether cancer cells can alter their temperature by regulating heat production. Non-shivering thermogenesis is known to takes place in inducible beige adipocytes expressing the mitochondrial thermogenic protein, uncoupling protein 1 (UCP1). UCP1 dissipates the proton gradient of the mitochondrial inner membrane and converts its energy into heat. We found that the inhibition of a hypoxia-inducible protein, fatty acid binding protein 7 (FABP7), triggered beige fat-like differentiation and induced thermogenesis in breast cancer cells. We established the breast cancer cell line with a stable knockdown of FAPB7, using lentivirus transduction particles. UCP1-expressing cells were found in 21 ± 5% of the knockdown cells while they were found in only 4 ± 1.7% of the control cells: p = 0.004). UCP1 expression was maximized in the knockdown cells when cultured in hypoxia. A novel thermo-sensitive fluorescent probe confirmed that the cellular temperature of the knockdown cells was 2°C higher than the controls. In addition, the knockdown cells exhibited the increased mitochondrial depolarization, increased proton leak and increased respiration rate compared to controls, suggesting they had the similar energy profile with beige adipocytes. The knockdown cells became more sensitive to hypoxia and radiation, and the clinical manifestation of breast cancer patients differed depending on the expression levels of both UCP1 and FABP7. These observations suggested a missing link between hypoxia-related fatty acid metabolism and cellular thermogenesis which might be a novel therapeutic target for breast cancer.

Citation Format: Masahiro Kawashima, Karim Bensaad, Christos Zois, Alessandro Barberis, Esther Bridges, Christoffer Lagerholm, Ruslan I. Dmitriev, Masakazu Toi, Dmitri B. Papkovsky, Francesca Buffa, Adrian L. Harris. Fatty acid binding protein 7 regulates beige fat-like differentiation of breast cancer cells and thermogenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3563.