To investigate the pathophysiology of cancer‐induced depression (
CID), we have recently developed a validated CIDmouse model. Given that the efficacy of antidepressants in cancer patients is controversial, it remains unclear whether CIDis a biologically distinct form of depression. We used RNA‐sequencing ( RNA‐seq) to investigate differentially expressed genes ( DEGs) in hippocampi of animals from our CIDmodel relative a positive control model of depressive‐like behavior induced with chronic corticosterone ( CORT). To validate RNA‐seq results, we performed quantitative real‐time RT‐PCR( qRT‐PCR) on a subset of DEGs. Enrichment analysis using DAVIDwas performed on DEGsto identify enriched Kyoto Encyclopedia of Genes and Genomes ( KEGG) pathways and biological process gene ontologies ( GO: BP). qRT‐PCRresults significantly predicted RNA‐seq results. RNA‐seq revealed that most DEGsidentified in the CORTmodel overlapped with the CIDmodel. Enrichment analyses identified KEGGpathways and GO: BPterms associated with ion homeostasis and neuronal communication for both the CORTand CIDmodel. In addition, CID DEGswere enriched in pathways and terms relating to neuronal development, intracellular signaling, learning and memory. This study is the first to investigate CIDat the mRNAlevel. We have shown that most hippocampal mRNAchanges that are associated with a depressive‐like state are also associated with cancer. Several other changes occur at the mRNAlevel in cancer, suggesting that the CIDmodel may represent a biologically distinct form of a depressive‐like state.