CEACAM1-4S, a cell–cell adhesion molecule, mediates apoptosis and reverts mammary carcinoma cells to a normal morphogenic phenotype in a 3D culture

Abstract

In a 3D model of breast morphogenesis, CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1) plays an essential role in lumen formation in a subline of the nonmalignant human breast cell line (MCF10A). We show that mammary carcinoma cells (MCF7), which do not express CEACAM1 or form lumena when grown in Matrigel, are restored to a normal morphogenic program when transfected with CEACAM1-4S, the short cytoplasmic isoform of CEACAM1 that predominates in breast epithelia. During the time course of lumen formation, CEACAM1-4S was found initially between the cells, and in mature acini, it was found exclusively in an apical location, identical to its expression pattern in normal breast. Lumena were formed by apoptosis as opposed to necrosis of the central cells within the alveolar structures, and apoptotic cells within the lumena expressed CEACAM1-4S. Dying cells exhibited classical hallmarks of apoptosis, including nuclear condensation, membrane blebbing, caspase activation, and DNA laddering. Apoptosis was mediated by Bax translocation to the mitochondria and release of cytochrome c into the cytoplasm, and was partially inhibited by culturing cells with caspase inhibitors. The dynamic changes in CEACAM1 expression during morphogenesis, together with studies implicating extracellular matrix and integrin signaling, suggest that a morphogenic program integrates cell-cell and cell-extracellular matrix signaling to produce the lumena in mammary glands. This report reveals a function of CEACAM1-4S relevant to cellular physiology that distinguishes it from its related long cytoplasmic domain isoform. mammary morphogenesis ͉ lumen formation

CEACAM1 (CD66a) mediates delay of spontaneous and Fas ligand-induced apoptosis in granulocytes

“…Notably, the importance of CEACAM in regulating apoptosis has been studied in various nongranulocytic cell types, and it has been found that CEACAM5 and CEACAM6 inhibit apoptosis [22], whereas CEACAM1 and CEACAM3 can induce apoptosis [20,23]. We therefore critically examined the apoptotic rate in PMN using three independent approaches: DNA fragmentation by PI staining, double-staining for annexin V and PI, and analyses of caspase-3 activity.…”

“…Anti-CEACAM1 antibodies and soluble recombinant CEA-CAM1-Fc fusion proteins are able to mimic these interactions [11,14]. Binding of these ligands to CEACAM1 induces signaling cascades which regulate cell proliferation [11], tumor growth [15], angiogenesis [16], differentiation of dendritic cells [17], T cell cytotoxicity [18], T cell-and B cell-mediated immune responses [12,19] and apoptosis [20]. Despite progress in the study of the functions of CEACAM1, its role in regulating the fate of granulocytes is still poorly understood.…”

The CEACAM1-mediated apoptosis pathway is activated by CEA and triggers dual cleavage of CEACAM1

“…A role of CEACAM1 has also been demonstrated in the morphogenesis and lumen formation of the human breast and transfection of MCF7 breast cancer cells with CEACAM1-4S induces massive apoptosis (Huang et al, 1999;Kirshner et al, 2003). Moreover, transient expression of CEACAM1-4L in MCF7 leads to rapid cell decay (unpublished data).…”

“…CEACAM1 plays an important role in the morphogenesis in human breast tissues where it is associated with apoptosis in differentiating epithelial cells (Huang et al, 1999;Kirshner et al, 2003). We recently demonstrated that crosslinking of CEACAM1 on the cell surface of tumour cells mediates apoptosis (Nittka et al, 2004).…”

The Cell-Cell Adhesion Molecule Carcinoembryonic Antigen-Related Cellular Adhesion Molecule 1 Inhibits IL-2 Production and Proliferation in Human T Cells by Association with Src Homology Protein-1 and Down-Regulates IL-2 Receptor

“…The 14-aa-short cytoplasmic domain lacks Tyr residues, but can be phosphorylated by protein kinase C on Ser and Thr residues (11) and binds calmodulin (CaM) (11) and both actin and tropomyosin (12). Recently, we have shown that CEACAM1-4S reverts breast cancer epithelial cells to a normal morphology and mediates lumen formation in a three-dimensional culture (13).…”