Gadd45a: an elusive yet attractive candidate gene in pancreatic cancer.

Introduction To date, pancreatic cancer remains one of the most lethal and least understood tumors known and is characterized as being resistant to most conventional chemotherapeutic regimens available (1). The fact that the etiology of this malignant gastrointestinal tumor is unknown, along with its invasive and metastatic properties, places a high priority on elucidating the molecular mechanism(s) underlying this disease with the aim of ultimately developing novel and effective therapeutic strategies to target this malignancy. Whereas effective therapies remain to be established, several molecular markers have been identified in the last decade, all of which are potential targets for future drug and/or genetic therapies. The vast majority of genes identified to date that have altered expression and/or mutations in pancreatic cancer are primarily oncogenes (such as K-ras), tumor suppressor genes (p16, p53, DPC, BRCA2, p300, MKK4, TGF1, TGF2, and so forth), or DNA repair genes [hMLH1 and hMSH2 (2)]. Some of these factors are directly involved in cell cycle regulation and apoptosis, whereas others are part of more complex signaling pathways mediating the conversion of cell surface signals into the activation of downstream cytoplasmic and nuclear factors (2, 3). In this issue of Clinical Cancer Research, Yamasawa et al. (4) identified Gadd45a (a growth arrest and DNA damage-inducible gene) as a new factor in the development of pancreatic cancer. This preliminary study identified point mutations in over 13% of tumors from 59 patients with invasive ductal carcinomas of the pancreas (Fig. 1). Moreover, overexpression of Gadd45a protein, along with possible p53 loss of function, significantly contributes to poor prognosis, compared with patients with undetectable Gadd45a. The relatively high mutation frequency in exon 4 of Gadd45a creates the need for a better understanding of this gene and to consider it as a novel target for future therapeutic measures. The purpose of this review is to present mechanistic insight into the potential roles of Gadd45a in protecting against tumorigenesis. The fact that mutations in either Tp53 or ATM genes in cancer-prone ataxia-telangiectasia patients result in decreased Gadd45a expression after IR draws an interesting correlation between Gadd45a and cancer. Cells derived from these patients demonstrate not only reduced p53 expression but also reduced Gadd45a expression (5). Additionally, Gadd45a has been found to associate with several cytoplasmic and nuclear factors and has been implicated in several cellular functions, including MAPK signaling (6), cell cycle regulation (7–9), DNA repair and genomic stability (10, 11), apoptosis (6), and immune responses (12). Defects in any one (or combination) of these processes may contribute to cancer.