Evidence of a role for loss of Bif-1 tumor suppressor activity in carcinogenesis has been found at the chromosomal level, in transcription, and in the protein product for a number of different cancers. The human Bif-1 gene is mapped to chromosome 1p22, a chromosome in which loss of heterozygosity (LOH) is frequently found in many tumor types (31
). As an example, a homozygous deletion of Bif-1 has been reported in mantle cell lymphomas (31
). Moreover, it has been shown that Bif-1 mRNA levels are down-regulated in lung carcinoma (40
) and colon cancer (41
). At the protein level, several reports described findings similar to ours, with subsets of tumors retaining Bif-1 expression, and others loosing such expression. For example, approximately 60% of gastric carcinoma [42
], 21% of prostate cancer [43
], 23% of colorectal adenocarcinoma [44
], and 15% of invasive bladder cancer [45
] are Bif-1 negative as determined by immunohistochemistry. Moreover, Bif-1 expression is down-regulated during clinical progression of breast carcinoma in situ to invasive and metastatic carcinomas [46
]. However, somatic mutation of bif-1 gene is rare in common human cancers [47
In this study, we found for the first time that Bif-1 was under-expressed in about 45% of pancreatic cancers, in contrast to the high levels normally expressed in nonmalignant pancreas. This novel finding is consistent with the function of Bif-1 as a tumor suppressor. However, it remains to be determined whether loss of Bif-1 tumor suppressor activity in pancreatic cancer would occur through reduced Bax activation with resultant decrease in apoptosis, inhibition of autophagy, or both.
As already noted, a number of the biochemical and molecular changes that occur in pancreatic cancer have been shown to be associated with differences in tumor behavior and clinical outcome. We found, however, that survival after pancreatectomy in patients who had low Bif-1 expression did not differ from survival in those who had the high level of Bif-1 expression most often found in non-malignant pancreas. Having failed to find that survival differed by Bif-1 expression, we considered that various histopathologic characteristics have been reported to be individually predictive of survival after pancreatectomy with curative intent. These characteristics include, but are not limited to, anatomic tumor extent as defined by AJCC staging, and tumor histologic characteristics. We recently reported that a simple combination of histopathologic characteristics reflecting aggressiveness of tumor biology (histologic differentiation, lymphatic invasion within the tumor, and local extrapancreatic tumor extension) was predictive of survival after pancreatectomy (48
). When we considered whether loss of Bif-1 expression might be associated with these and other potentially adverse histopathologic characteristics, we were unable to find an association.
Loss of Bif-1 expression in a subset of patients with ductal pancreatic cancer is presumptive evidence of a role for loss of Bif-1 tumor suppressor activity in pancreatic carcinogenesis. Yet, we were unable to demonstrate an association between loss of Bif-1 expression and clinical outcome, a finding that may be best explained by the complexity of carcinogenesis. For example, one explanation might be that loss of Bif-1 tumor suppressor activity may be more important in earlier stages of carcinogenesis, while factors other than loss of Bif-1 tumor suppressor activity may dominate the outcome after pancreatectomy. Nevertheless, finding a loss of Bif-1 expression in pancreatic adenocarcinoma is an important step in understanding the biology of the disease, and one which may help design new targeted molecular strategies for treatment of a cancer that has been resistant to therapy thus far.