Sphingolipids as mediators of breast cancer progression, metastasis, response and resistance to chemotherapy

Approximately 250,000 people are diagnosed with breast cancer and 40,000 people die from the disease annually in the United States. Significant effort has been put into developing a thorough understanding of the molecular and genetic events that contribute to tumor progression due to mounting evidence that breast cancers are driven by predictable and identifiable genetic mutations, Sphingolipids modulate many of the growth, apoptosis, inflammatory, and angiogenic pathways that breast carcinomas rely on. Recent work in the field of sphingolipidomics has identified many key roles for the sphingolipids in breast tumor progression and identified signaling roles in each of the molecular subtypes of breast cancer. For example, in luminal type tumors, increased expression of ceramide producing enzymes and high levels of complex sphingolipids are associated with poor outcomes and multi-drug resistance. In basal type breast tumors CERT and GCS play a role in resistance to taxanes suggesting that targeting these pathways may be an effective route for the treatment of aggressive triple negative tumors. The role of sphingolipids in Her2-like tumors has not been thoroughly studied. However, CERK has been identified as potential driver of Her2-like tumors. Clearly, sphingolipid signaling in tumor modulation is both complex and vital. By integrating sphingolipid signaling into the molecular characterization of breast tumors, new opportunities for targeted intervention are identified. It is increasingly apparent that modulating sphingolipid levels in tumors will be an effective and powerful method for the treatment of breast cancer.