Disruption of hypoxia-inducible fatty acid binding protein 7 induces beige fat-like differentiation and thermogenesis in breast cancer cells.
Kawashima M., Bensaad K., Zois CE., Barberis A., Bridges E., Wigfield S., Lagerholm C., Dmitriev RI., Tokiwa M., Toi M., Papkovsky DB., Buffa FM., Harris AL.
Background: Humans produce heat through non-shivering thermogenesis, a metabolic process that occurs in inducible beige adipocytes expressing uncoupling protein 1 (UCP1). UCP1 dissipates the proton gradient of the mitochondrial inner membrane and converts that energy into heat. It is unclear whether cancer cells can exhibit autonomous thermogenesis. Previously, we found that the knockdown of hypoxia-inducible fatty acid binding protein 7 (FABP7) increased reactive oxygen species (ROS) in breast cancer cells. ROS are known to induce beige adipocyte differentiation. Methods: We investigated the association of tumor hypoxia, FABP7, and UCP1 across breast cancer patients using METABRIC and TCGA data sets. Furthermore, using a breast cancer cell line, HCC1806, we tested the effect of FABP7 knockdown on cellular physiology including thermogenesis. Results: We found a strong mutual exclusivity of FABP7 and UCP1 expression both in METABRIC and in TCGA, indicating major metabolic phenotypic differences. FABP7 was preferentially distributed in poorly differentiated-, estrogen receptor (ER) negative tumors. In contrast, UCP1 was highly expressed in normal ducts and well-differentiated-, ER positive-, less hypoxic tumors. In the cell line-based experiments, UCP1 and its transcriptional regulators were upregulated upon FABP7 knockdown. UCP1 was induced in about 20% of cancer cells, and the effect was increased further in hypoxia. UCP1 depolarized mitochondrial membranes at the site of expression. UCP1 induction was associated with the increase in proton leak, glycolysis, and maximal respiration, mimicking the typical energy profile of beige adipocytes. Most importantly, UCP1 induction elevated cancer cell temperature associated with increased vulnerability to hypoxia and γ-irradiation. Conclusions: We demonstrated that breast cancer cells can undergo thermogenesis through UCP1 induction. Disrupting FABP7-mediated fatty acid metabolism can unlock UCP1-mediated thermogenesis, potentially making it possible to develop therapies to target thermogenesis. Further study would be warranted to investigate the effect of rise in temperature of cancer cells on patients' outcomes and the relationship to other metabolic pathways.