Loss of Ceacam1 promotes prostate cancer progression in Pten haploinsufficient male mice

PTEN haploinsufficiency plays an important role in prostate cancer development in men. However, monoallelic deletion of Pten gene failed to induce high prostate intraepithelial neoplasia (PIN) until Pten+/− mice aged or fed a high-calorie diet. Because CEACAM1, a cell adhesion molecule with a potential tumor suppression activity, is induced in Pten+/− prostates, the study aimed at examining whether the rise of CEACAM1 limited neoplastic progression in Pten+/− prostates. Pten+/− were crossbred with Cc1−/− mice harboring a null deletion of Ceacam1 gene to produce Pten+/−/Cc1−/− double mutants. Prostates from 7-month old male mice were analyzed histologically and biochemically for PIN progression. Deleting Ceacam1 in Pten+/− mice caused an early development of high-grade PIN in parallel to hyperactivation of PI3 kinase/Akt and Ras/MAP kinase pathways, with an increase in cell proliferation, epithelial-to-mesenchymal transition, angiogenesis and inflammation relative to Pten+/− and Cc1−/− individual mutants. It also caused a remarkable increase in lipogenesis in prostate despite maintaining insulin sensitivity. Concomitant Ceacam1 deletion with Pten+/− activated the IL-6/STAT3 signaling pathways to suppress Irf-8 transcription that in turn, led to a decrease in the expression level of promyelocytic leukemia gene, a well characterized tumor suppressor in prostate. Ceacam1 deletion accelerated high-grade prostate intraepithelial neoplasia in Pten haploinsufficient mice while preserving insulin sensitivity. This demonstrated that the combined loss of Ceacam1 and Pten advanced prostate cancer by increasing lipogenesis and modifying the STAT3-dependent inflammatory microenvironment of prostate. •CEACAM1-4L expression is elevated in prostates of Pten+/− mice.•Ceacam1 deletion causes progression of neoplasia in prostates of Pten+/− mice.•Ceacam1 deletion causes EMT and angiogenesis in prostates of Pten+/− mice.•Ceacam1 deletion causes lipogenesis and inflammation in prostates of Pten+/− mice.•Ceacam1 deletion activates STAT3 to limit Irf-8 and Pml transcription in Pten+/−.