BMC Cancer 2008, 8:270 http://www.biomedcentral.com/1471-2407/8/270 The nuclear activity characterizing the highly expressed genes in the papillary adenocarcinoma was not found in the carcinoma tumors. On the other hand, many of the highly expressed genes in the latter tumors encode cytosolic binding proteins: cytoskeletal binding proteins, heparin-binding proteins, GTP-binding proteins, and cal- cium ion-binding proteins. The stronger expression of these regulatory genes may complement the better inter- actions of the carcinoma cells with the ECM, as depicted by the higher expression of genes coding for several key integrins. Interestingly, genes with higher expression in the carcinoma tumors, but with a generally lower level of expression, are the backbone of the favored actin-cytoskel- eton activity. Categorization of the genes according to their involve- ment in particular metabolic functions served to highlight several pathways. Genes involved in ECM-receptor inter- actions and the focal-adhesion pathway encode proteins of the cell-adhesion sites that are involved in cell detach- ment and actin-cytoskeleton activities. Most of these genes were more highly expressed in the carcinoma tumors, implicating a higher potential for cell adhesion, membrane protrusion, spreading and migration in these tumors [45]. Since tumors developed in mouse models rarely metastasize [46], the expression profile of these genes may unveil the cryptic motility and metastatic potential of the carcinoma tumors. The stronger expres- sion of N-acetylglucosaminyltransferases and sialyltrans- ferases in the carcinoma tumors potentially augments the anti-adhesive effect of Muc1 and Muc 4, and contributes to tumor progression [44,47]. Cav-1 is also involved in cell adhesion [48] and was expressed at higher levels in the carcinoma tumors than in the papillary adenocarcinomas. Its external expression in the membrane of the basal epithelial cells comprising the neoplastic mass of the carcinoma vs. its internal localiza- tion within the papillary fibrovascular core exemplifies the possible involvement of intracellular compartmental- ization of gene expression in the determination of tumor phenotypes. The differential expression of the genes comprising the Wnt pathways led to augmentation of β-catenin in the cytoplasm of the papillary adenocarcinomas as compared to its nuclear translocation in the carcinoma tumors. Accumulation of β-catenin in the cytosol of the mammary tumor cells and formation of cadherin-catenin complexes have been reported to induce cell polarity, survival and more controlled cell proliferation. Those factors are man- datory for assuming a specific shape within the tissue [49] and most likely induce the unique shaping of the papil- lary adenocarcinoma. High expression of VASP and formin-binding protein in the papillary adenocarcinoma triggers long unbranched filaments termed filopodia, which are frequently observed in cell-cell contacts [50]. When the cadherin-catenin complex is less engaged, such as in the carcinoma, cell death and increased proliferation occur, as well as enhanced migration [49,50]. The Notch pathway regulates the development of postna- tal and adult tissues [33]. It has been suggested that its tumor-promoting activity results from its involvement in restricting differentiation towards alternate fates and thereby allowing self-renewal and survival of relatively undifferentiated cells. However, Notch may also exert an anti-proliferative effect via the activation of p21 [51]. Our array analysis indicated distinct expression patterns for genes involved in the Notch pathway in the two types of tumors. The carcinomas exhibited higher expression of the Jagged and Dll1 ligands, as well as of members of the γ-secretase complex which allow their nuclear transloca- tion, and increased Wnt signaling towards cell prolifera- tion [34]. In the papillary adenocarcinoma, however, stronger expression of the Notch-1 receptor was observed and the higher expression of Fringe favors its activation by the Dll rather than Jagged ligand. The role of this pattern of gene expression in specific properties of the papillary adenocarcinoma tumors has yet to be determined. Simi- larly, the higher expression of Smad4 in the papillary ade- nocarcinoma tumors as potential compensation for the better expression of members the TGF-β-Smad3 pathway in the carcinomas has to be elucidated. Differences were also demonstrated in the regulation of cell-cycle activity in the two tumors. Genes involved in G1 arrest and DNA repair were more highly expressed in the papillary adenocarcinoma. In contrast, G2/M arrest, mainly via Cdc2/cyclin B, was favored in the carcinoma tumors. The earlier induction of genes involved in DNA damage, repair and senescence in the papillary adenocar- cinoma may account for this tumor's less aggressive phe- notype [52]. Our results provide evidence that the poorly differentiated mammary carcinoma and highly differentiated papillary adenocarcinoma represent biologically distinct disease entities. Both types were developed in transgenic mice expressing either the constitutively active Stat5 or its C-ter- minally truncated counterpart. Manipulation of Stat5 lev- els and activity during the fertile period in transgenic females may leave a mark on the gene-expression profile in the developing tumors [14]. Together with accumu- lated microenvironmental and genetic effects, it contrib- utes to the establishment of unique tumor phenotypes. To this end, our analysis suggests that specific differences in gene expression profiles and resulting metabolic path- ways contribute to maintaining the carcinoma and papil- lary adenocarcinoma tumor phenotypes, regardless the Page 16 of 19 (page number not for citation purposes)