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Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a glycoprotein that is part of the carcinoembryonic antigen and the immunoglobulin superfamilies. We have shown that it functions as a tumor suppressor and that this function depends upon the presence of the longer CEACAM1 cytoplasmic domain. In this report, we describe the generation of a Ceacam1-/- mouse. The Ceacam1-/- colon exhibits increased in vivo proliferation relative to the wild-type counterpart with a corresponding decreased expression of the p21(Cip1) and p27(Kip1) Cyclin D kinase inhibitors. The colonic villi undergo decreased apoptosis. Out of 35 litters of mice, no spontaneous tumors in any tissues normally expressing CEACAM1 were found over the lifespan of the animals, suggesting that CEACAM1 may not be involved in initiation of tumor development. However, when mice are treated with azoxymethane to induce colonic tumors, we find that Ceacam1-/- mice developed a significantly greater number of tumors than their littermate controls. Moreover, the tumor size was greater in the knockout mice relative to that in the wild-type mice. These results indicate that deletion of CEACAM1 favors progression of colon tumorigenesis.

Introduction c-Jun activation domain-binding protein-1 (Jab1) is a multifunctional signaling protein that previously has been shown to be a master regulator of a poor prognostic gene signature in invasive breast cancer and to mediate the action of S100A7. Since epidermal growth factor receptor (EGFR), like S100A7, is often expressed in estrogen receptor-alpha-negative (ERα-) breast cancer, we set out to investigate the role of Jab1 in mediating EGFR signaling, another facet of the ERα- phenotype. Methods MDA-MB-231 and MDA-MB-468 ERα-/EGFR+ cell lines were assessed for localization of Jab1 and levels of downstream genes by immunofluorescence and nuclear protein extract assay following treatment with epidermal growth factor (EGF) and extracellular signal-regulated kinase (ERK) pathway inhibitor. A cohort of 424 human breast tumors was also assessed by immunohistochemistry. Results EGF treatment of cell lines resulted in increased Jab1 nuclear expression. This effect was inhibited by the ERK pathway inhibitor, PD98059. EGF treatment was also associated with colocalization of pERK (phosphorylated ERK) and Jab1 as well as regulation of the Jab1 downstream target gene, p27. When Jab1 activity was knocked down, p27 levels were restored to pre-EGF treatment level. Analysis of EGFR and Jab1 expression in a cohort of invasive breast tumors by tissue microarray and immunohistochemistry confirmed a relationship between EGFR and increased nuclear Jab1 within the ERα- subset (n = 154, P = 0.019). The same association was also confirmed for S100A7 and Jab1 (P = 0.036), and high Jab1 nuclear expression was most frequent in tumors that were positive for both EGFR and S100A7 (P = 0.004). Conclusion Jab1 is a target of EGFR signaling in ERα- cell lines and breast tumors and therefore may be a common central factor and potential therapeutic target for important cell signaling pathways in ERα- breast cancer.