Cancer develops from overlapping events that tend to deregulate the metabolism and unbalance the homeostasis of cells. Sphingolipids, major components of biological membranes, are also mediators of intracellular signalling. Their metabolism can be influenced by diverse stimuli and the accumulation or deficiency of intermediates may trigger proliferation and/or impair the ability of damaged cells to undergo apoptosis. Many sphingolipid-regulated functions are implicated in tumour initiation, promotion, progression and responsiveness to chemotherapy. In this review, evidence of the alteration of sphingolipids metabolism and signalling will be discussed in breast cancer prevention and therapy.

Various lipidic molecules serve as second messengers for transducing signals from the cell surface to the cell interior and trigger specific cellular responses. Sphingolipids represent a complex group of lipids that have recently emerged as new transducers in eukaryotic cells. Several sphingolipid molecules are able to modulate cell growth, differentiation and death. This review summarises current knowledge of the signalling functions of sphingolipids, especially in the regulation of tumour necrosis factor α (TNF-α)-mediated cytotoxic effects. TNF-α is a multifaceted cytokine that controls a wide range of immune responses in mammals, including induction of programmed cell death (also called apoptosis). On the basis of recent observations, a working model is proposed for the molecular mechanisms underlying regulation of sphingolipid generation following TNF-α receptor 1 activation. The implications of these findings for the development of future pharmacological strategies to prevent the cytotoxic TNF-α response and subsequent cellular dysfunctions (as seen in various human diseases) are discussed.