Neutral Sphingomyelinase in Breast Cancer

PROJECT SUMMARY Bioactive sphingolipids including ceramide (Cer), constitute a family of related molecules implicated in many processes pertinent to tumorigenesis. Because of its pro-death and anti-growth functions, we have proposed Cer to function as a tumor suppressor lipid, yet our ability to mechanistically define its role in tumor behavior has been hampered by lack of molecular tools. This proposal builds on recent studies and results that have identified neutral sphingomyelinase-2 (N2), a key Cer-producing enzyme, as an epigenetically suppressed gene in in breast cancer (BC) and that it displays tumor suppressor functions in cells and in vivo. Based on these novel data, we advance the hypothesis that N2 is an important tumor suppressor enzyme, acting through Cer and downstream signaling pathways to suppress anchorage-independent growth (AIG) and to prevent BC progression and metastasis. This also offers specific therapeutic potential by ‘reactivating’ the N2 pathway and/or exploiting it in synthetic lethality studies. This hypothesis will be tested by pursuing the following specific aims: In Aim 1, we will establish N2 as a tumor suppressor in vivo, define its role in AIG, and define the mechanisms of its action with a specific emphasis on YAP/TAZ driven signaling. In Aim 2, we will advance the N2 pathway as a novel target in BC taking a two-pronged approach: 2a) define the ‘reciprocal’ enzyme(s) that metabolizes N2-generated Cer and develop it as therapeutic targets; and 2b) identify targets that are synthetically lethal with loss (suppression) of N2. Taken together, these results will define the N2/Cer pathway as a novel tumor suppressor pathway with a key function in suppressing AIG, a hallmark of transformation that is surprisingly understudied. Our studies will further dissect novel mechanisms of N2 action, through a heretofore unappreciated link of Cer to the Yap/Taz pathway. Finally, these studies will also advance the N2/Cer axis as a viable therapeutic target through innovative strategies.