Abstract. Both carcinoembryonic antigen (CEA) and neural cell adhesion molecule (NCAM) belong to the immunoglobulin supergene family and have been demonstrated to function as homotypic Ca ++-independent intercellular adhesion molecules. CEA and NCAM cannot associate heterotypically indicating that they have different binding specificities. To define the domains of CEA involved in homotypic interaction, hybrid cDNAs consisting of various domains from CEA and NCAM were constructed and were transfected into a CHO-derived cell line; stable transfectant clones showing cell surface expression of CEA/NCAM chimeric-proteins were assessed for their adhesive properties by homotypic and heterotypic aggregation assays. The results indicate that all five of the Ig(C)-like domains of NCAM are required for intercellular adhesion while the COOH-terminal domain containing the fibronectin-like repeats is dispensable.The results also show that adhesion mediated by CEA involves binding between the Ig(V)-like aminoterminal domain and one of the Ig(C)-like internal repeat domains: thus while transfectants expressing constructs containing either the N domain or the internal domains alone were incapable of homotypic adhesion, they formed heterotypic aggregates when mixed. Furthermore, peptides consisting of both the N domain and the third internal repeat domain of CEA blocked CEA-mediated cell aggregation, thus providing direct evidence for the involvement of the two domains in adhesion. We therefore propose a novel model for interactions between immunoglobulin supergene family members in which especially strong binding is effected by double reciprocal interactions between the V-like domains and C-like domains of antiparallel CEA molecules on apposing cell surfaces.C ELL-cell interactions mediated by intercellular adhesion molecules (CAMs) ~ are essential for numerous cellular responses, ranging from cell-mediated immune responses to the sorting of heterogeneous cell populations into organized arrays during tissue formation in organogenesis (Armstrong, 1989). A major proportion of known CAMs to date belong to the Ig gene superfamily (Williams and Barclay, 1988). This family of molecules is involved in many different types of cell surface recognition events, including specific intercellular adhesion (Edelman, 1985). Common to these molecules is the Ig homology unit which consists of two/3 sheets stabilized by disulfide bonds. Based on primary sequence similarities and secondary structure predictions, three homology unit types have been Please address all correspondence to Dr. C. P. Stanners, McGill Cancer Centre, 3655 Drummond Street, Montreal, Quebec, Canada H3G 1Y6.1. Abbreviations used in this paper: CAMs, intercellular adhesion molecules; CKS, CMP-KDO synthetase; GPI, glyco-phosphatidylinositol; GPI-PLC, glycophosphatidylinositol phospholipase C; NCAM, neural cell adhesion molecule; TFMS, trifluoromethanesulfonic acid. defined: the variable like-domain (V-set) and two constant like-domains (Cl-set or C2-set) (Williams and Barclay, 1...

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Co-amplification at chromosomes 8p11-8p12 and 11q12-11q14 occurs often in breast tumors, suggesting possible cooperation between genes in these regions in oncogenesis. We used high resolution array comparative genomic hybridization (array CGH) to map the minimal amplified regions. The 8p and 11q amplicons are complex and consist of at least four amplicon cores at each site. Candidate oncogenes mapping to these regions were identified by combining copy number and RNA and protein expression analyses. These studies also suggested that CCND1 at 11q13 induced expression of ZNF703 mapping at 8p12, which was subsequently shown to be mediated via the Rb/E2F pathway. Nine candidate oncogenes from 8p12 and four from 11q13 were further evaluated for oncogenic function. None of the genes individually promoted colony formation in soft agar or collaborated with each other functionally. On the other hand, FGFR1 and DDHD2 at 8p12 cooperated functionally with MYC, while CCND1 and ZNF703 cooperated with a dominant negative form of TP53. These observations highlight the complexity and functional consequences of the genomic rearrangements that occur in these breast cancer amplicons, including transcriptional cross-talk between genes in the 8p and 11q amplicons, as well as their cooperation with major pathways of tumorigenesis.