Emerging Roles of Ceramides in Breast Cancer Biology and Therapy

Abstract

One of the classic hallmarks of cancer is the imbalance between elevated cell proliferation and reduced cell death. Ceramide, a bioactive sphingolipid that can regulate this balance, has long been implicated in cancer. While the effects of ceramide on cell death and therapeutic efficacy are well established, emerging evidence indicates that ceramide turnover to downstream sphingolipids, such as sphingomyelin, hexosylceramides, sphingosine-1-phosphate, and ceramide-1-phosphate, is equally important in driving pro-tumorigenic phenotypes, such as proliferation, survival, migration, stemness, and therapy resistance. The complex and dynamic sphingolipid network has been extensively studied in several cancers, including breast cancer, to find key sphingolipidomic alterations that can be exploited to develop new therapeutic strategies to improve patient outcomes. Here, we review how the current literature shapes our understanding of how ceramide synthesis and turnover are altered in breast cancer and how these changes offer potential strategies to improve breast cancer therapy.

Keywords: apoptosis; breast cancer; ceramides; drug resistance; sphingolipids.

Figure 1

Structures of ceramides and other sphingolipids. (A) The most prevalent sphingoid base in mammals is a C18-sphingosine. General structures of ceramides (B), sphingomyelins (C) and glucosylceramides (D) on the C18-sphingoid backbone (black). Head groups of sphingomyelin and glucosylceramides are shown in blue. The acyl chain (red) length varies from 16 to 26 carbon-containing structures, predominantly in mammalian cells. C16 species are shown here as representative structures.

Figure 2

Ceramide production and turnover pathways. Enzymes are depicted in gray. Pro-apoptotic sphingolipids are depicted in red, and pro-proliferative sphingolipids are depicted in green. Diagram was created with Biorender.com.