3p21.31

CD318,SIMA135,TRASK

Tumorigenesis

Expression and phosphorylation in tumors
The expression of CDCP1 relative to the normal epithelium is reduced or lost in some tumors, particularly in breast, colon, prostate and lung cancers (Wong et al., 2009; Spassov et al., 2012). This is due to loss of heterozygosity in CDCP1 genomic region and/or promoter methylation (Spassov et al., 2012). CDCP1 is widely and abundantly expressed in human epithelial tissues, but its phosphorylation is not detectable in normally anchored epithelial layers (Spassov et al., 2009). However, phosphorylation of CDCP1 is seen in many epithelial tumors from all stages including early stage carcinomas, invasive, and metastatic tumors (Wong et al., 2009). The phosphorylation of CDCP1 in tumors suggests that they may exist at an abnormal or deficient state of anchorage in vivo (Spassov et al., 2011). This may be due to abnormalities in the composition of the surrounding matrix, defective assembly of adhesion complexes, or defective signaling through the integrin adhesion complex. Specifically, this may be due to the absence of a continuous basal lamina which typically underlies the basal surface of epithelial cells in the normal epithelium but is highly abnormal or missing in epithelial tumors.
Animal model
Mice lacking CDCP1 do not exhibit gross morphologic, reproductive or behavioral abnormalities compared with wild-type mice, and histologic examination of multiple organ systems found no significant pathology and no observed histologic differences (Spassov et al., 2013). Mammary tumors driven by the PyMT oncogene and skin tumors driven by activation of Hedgehog pathway developed with accelerated kinetics in CDCP1 null mice, establishing a tumor suppressing function for this gene during cancer initiation and evolution (Spassov et al., 2013). Mechanistic investigations in mammary tumor cell lines derived from CDCP1-deficient mice revealed a de-repression of integrin signaling and an enhancement of integrin-growth factor receptor cross-talk; hence increased growth factor signaling and cell proliferation of CDCP1 null cancer cells (Spassov et al., 2013).
Metastasis
The role of CDCP1 in cellular migration may suggest a potential role of this gene in cancer metastasis. However, this role may be a complex one, considering that both loss of function and gain of function of CDCP1 inhibit migratory capacity of the cells. Inducible expression and phosphorylation of CDCP1 in breast cancer MCF7 cell line decreased the number of lymph node metastasis after orthotopic mammary fat pad implantation (Spassov et al., 2012). Similarly, the inducible expression of CDCP1 in v-src transformed NIH3T3 cells significantly decreased the lung colonization capacity of the cells after tail vein inoculation (Spassov et al., 2012). Knockdown of CDCP1 have also been reported to decrease experimental metastasis of lung and melanoma cell lines (Uekita et al., 2007; Liu et al., 2011). Future work is required to elucidate the functions of CDCP1 in cancer metastasis and whether there will be clinical benefits of targeting this gene. Several efforts have been made to target CDCP1 with monoclonal antibody that recognizes the extracellular domain of the protein. Such antibodies induce the phosphorylation of CDCP1 and have been shown to suppress experimental metastasis in preclinical models (Siva at al., 2008; Casar et al., 2012). It is unclear if this is due to effects on CDCP1 function or if it is mediated through immunological mechanisms.

No hybrid genes, containing CDCP1 are known.

No fusions with CDCP1 have been reported.

CDCP1 null mice show accelerated oncogenesis in genetically modified experimental models of skin and breast cancers.