Gene Expression Profiling of Triple Negative Breast Cancer Cells Responding to Adipocyte Secreted Factors

Adipocyte-secreted factors (ASFs) induce lipid accumulation in breast cancer cells. These lipid droplets are thought to serve a cell-protective, pro-oncogenic role. ASFs including insulin, CCL5, and apelin interact with receptors that stimulate mTOR signaling in neighboring cells. One of the major transcription factors that acts downstream of this signaling pathway is SREBP1, which translocates into the nucleus and activates the expression of metabolic enzymes and other proteins involved in fatty acid synthesis, transport, and storage. Their associated enzymatic activities increase or decrease pools of metabolites that serve as substrates and cofactors for chromatin remodeling, such as acetyl-CoA, alpha-ketoglutarate (α-KG), flavin adenine dinucleotide (FAD+), and nicotinamide adenine dinucleotide (NAD+), but the impact on gene regulation in this context is not completely understood. To model biochemical signaling from adipocytes to breast cancer epithelial cells, we cultured differentiated mouse OP-9 cells, collected the adipocyte conditioned medium (ACM) after three days, and treated human breast epithelial BT-549 cells with ACM. Three days after treatment, we observed accumulation of lipid droplets in the cytoplasm of most BT-549 cells, whereas none were visible in cells grown in unconditioned medium (UCM). Transcription profiling verified the activation of lipid droplet biosynthesis genes, and revealed repression of loci at every chromosome, consistent with the idea that lipogenesis affects the availability of substrates and cofactors for global chromatin remodeling.