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 (DTC) 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 upregulated during
tumor recurrence in multiple genetically engineered mouse models for
breast cancer. We find that Cerk is rapidly upregulated in
tumor cells following HER2/neu downregulation or treatment with
Adriamycin and that Cerk is required for
tumor cell survival following HER2/neu downregulation. Consistent with our observations in mouse models, analysis of gene expression profiles from more than 2,200 patients revealed that elevated CERK expression is associated with an increased risk of recurrence in women with
breast cancer. In addition, although CERK expression is associated with aggressive subtypes of
breast cancer, including those that are
estrogen receptor-negative, HER2(+), basal-like, or high grade, its association with poor clinical outcome is independent of these clinicopathologic variables. Together, our findings identify a functional role for Cerk in
breast cancer recurrence and suggest the clinical utility of agents targeted against this prosurvival pathway.