Human CDX2 (hCDX2), one of three caudal-related homeodomain transcription factors, was contemporaneously cloned in 1997 by Drummond et al.^[1] and Mallo et al.^[2] from an adult jejunal cDNA library and by differential screening of mRNA from colorectal cancer and normal adjacent mucosa, respectively. FISH analysis mapped hCDX2 to chromosome 13q12-q13^[1]. Putative post-transcriptional processing of the three exon hCDX2 gene generates a 313 amino acid protein containing an amino-terminal activation domain and a carboxyl-terminal homeobox binding domain. In rodents, the amino-terminal region has been shown to regulate nuclear translocation^[3] and modifying transcriptional activity^[4]. The homeodomain binds as either a monomer or dimer to the DNA sequence(s) TTTAT/C^[5] in gene enhancer and promoter regions to initiate or repress gene transcription^[6]. In mouse embyros, the expression of Cdx2 during pre- and early postimplantation is limited to the TE lineage where it represses expression of Oct4 and Nanog^[7][8]. Similarly, in primate embryos, reduced expression of CDX2 results in the generation of a non-functional trophectoderm^[9] suggesting a critical role for early embryogenesis. In adult humans CDX2 is specifically expressed by epithelial cells lining the small and large intestine. Trans-acting factors that regulate CDX2 expression include OCT1^[10], NF-KB^[11], and CDX2^[12] itself. CDX2 regulates development and maintenance of the intestinal epithelium by binding DNA and recruiting co-factors, such as p300^[13], thereby initiating or repressing expression of genes involved in proliferation^[14], differentiation^[14], cell-cell adhesion^[15][16], apoptosis, and cell cycle control^[17]. Consistent with its role in regulating intestinal homeostasis, CDX2 has been shown to play a role in the homeostatic Notch^[18] and Raf-Mek-Erk 1/2^[19] signaling pathways.

The role of hCDX2 in the development and progression of colorectal tumors is controversial. Early data suggested that loss of hCDX2 was a common event in tumorigenesis^[2]. However, subsequent studies have shown that expression of hCDX2 as well as many of its down-stream targets such as guanylyl cyclase C are retained and in some cases over-expressed in tumors^[20], with the exception of a subset of poorly differentiated tumors with a high frequency of microsatellite instability^[21]. In vitro data also provides conflicting evidence supporting the role of CDX2 as a tumor suppressor. For example, CDX2 has been shown to inhibit proliferation and induce differentiation. However, it has also been shown to increase anchorage-independent growth and survival by binding and repressing expression of the growth inhibitor insulin-like growth factor binding protein-3 (IGFBP-3)^[22]. thereby suggesting tumorigenic potential. Further studies will most likely define the contexts that influence the role CDX2 assumes.

Ectopic expression of hCDX2 has been demonstrated to precede the development of esophageal and gastric intestinal metaplasia and is retained in adenocarcinomas arising therein^[11][23][11]. Similar to colorectal carcinogenesis, the role of ectopically expressed hCDX2 in upper gastrointestinal tumors remains undefined. The two conflicting paradigms suggest that hCDX2 is either ectopically expressed to generate an intestine-like epithelium that is protective against insults such as bile acid reflux. The competing hypothesis propounds that hCDX2 expression generates an unstable epithelium predisposed to neoplastic transformation. Given the numerous downstream targets and pathways that hCDX2 influences, its role in tumorigenesis is most likley multifactorial making generalizations about its role in inhibiting or promoting gastrointestinal tumor growth difficult to define.

Immunohistochemical detection of hCDX2 protein has been documented in extra-intestinal tumors with intestinal morphology including ovary^[24], bladder^[25], and lung^[26]. A role for hCDX2 in hematopoiesis and hematologic malignancies has also been recently demonstrated^[27]. Although CDX2 expression has been demonstrated in some non-gastrointestinal tumors, the immunohistochemical detection of CDX2 has become an important tool for pathologists in the confirmation of the gastrointestinal tract as a primary site of malignancies.