Ceramide Kinase Promotes Tumor Cell Survival and Mammary Tumor Recurrence

Abstract

Recurrent breast cancer is typically an incurable disease and, as such, is disproportionately responsible for deaths from this disease. Recurrent breast cancers arise from the pool of disseminated tumor cells (DTCs) that survive adjuvant or neoadjuvant therapy, and patients with detectable DTCs following therapy are at substantially increased risk for recurrence. Consequently, the identification of pathways that contribute to the survival of breast cancer cells following therapy could aid in the development of more effective therapies that decrease the burden of residual disease and thereby reduce the risk of breast cancer recurrence. We now report that Ceramide Kinase (Cerk) is required for mammary tumor recurrence following HER2/neu pathway inhibition and is spontaneously up-regulated during tumor recurrence in multiple genetically engineered mouse models for breast cancer. We find that Cerk is rapidly up-regulated in tumor cells following HER2/neu down-regulation or treatment with Adriamycin and that Cerk is required for tumor cell survival following HER2/neu down-regulation. Consistent with our observations in mouse models, analysis of gene expression profiles from over 2,200 patients revealed that elevated CERK expression is associated with an increased risk of recurrence in women with breast cancer. Additionally, although CERK expression is associated with aggressive subtypes of breast cancer, including those that are ER–, HER2+, basal-like, or high grade, its association with poor clinical outcome is independent of these clinicopathological variables. Together, our findings identify a functional role for Cerk in breast cancer recurrence and suggest the clinical utility of agents targeted against this pro-survival pathway.

RIPK3 upregulation confers robust proliferation and collateral cystine-dependence on breast cancer recurrence

“…To identify differentially expressed genes important for tumor recurrence, we have previously performed microarrays to compare the differences in the transcriptome landscape between primary and recurrent tumor cells (GEO: GSE116513) 24 . This comparison validates the previously reported upregulation of Ceramide Kinase ( Cerk ) 25 and downregulation of Prostate Apoptosis Response 4 ( Par-4 ) 26 in the recurrent tumor cells (Figure 1A). Also, recurrent tumor cells expressed a higher level of EMT-driving Snail Family Transcriptional Repressor 1 ( Snai1 ), 13 (Figure 1A), consistent with an enrichment of EMT by Gene Set Enrichment Analysis (GSEA) (Figure 1B).…”

Identification of an acid sphingomyelinase ceramide kinase pathway in the regulation of the chemokine CCL5 [S]

“…In breast cancers, expression of both CERK and TNF-α is associated with poor outcomes (54)(55)(56). The microenvironment is shaped and defined by pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6 and CCL5 (30, 57-60).…”

Sphingolipid metabolism in cancer signalling and therapy

“…Increased CERK–C1P signalling promoted breast cancer cell survival and mammary tumour recurrence following HER2 inhibition in mouse models 58 . Moreover, a CERK inhibitor, NVP-231, inhibited breast and lung cancer cell proliferation by inducing ceramide-mediated cell cycle arrest and apoptosis 59 .…”