Expression of HOXB2, a Retinoic Acid Signaling Target in Pancreatic Cancer and Pancreatic Intraepithelial Neoplasia

Abstract

Purpose: Despite significant progress in understanding the molecular pathology of pancreatic cancer and its precursor lesion: pancreatic intraepithelial neoplasia (PanIN), there remain no molecules with proven clinical utility as prognostic or therapeutic markers. Here, we used oligonucleotide microarrays to interrogate mRNA expression of pancreatic cancer tissue and normal pancreas to identify novel molecular pathways dysregulated in the development and progression of pancreatic cancer. Experimental Design: RNA was hybridized to Affymetrix Genechip HG-U133 oligonucleotide microarrays. A relational database integrating data from publicly available resources was created to identify candidate genes potentially relevant to pancreatic cancer. The protein expression of one candidate, homeobox B2 (HOXB2), in PanIN and pancreatic cancer was assessed using immunohistochemistry. Results: We identified aberrant expression of several components of the retinoic acid (RA) signaling pathway (RARa, MUC4, Id-1, MMP9, uPAR, HB-EGF, HOXB6, and HOXB2), many of which are known to be aberrantly expressed in pancreatic cancer and PanIN. HOXB2, a downstream target of RA, was up-regulated 6.7-fold in pancreatic cancer compared with normal pancreas. Immunohistochemistry revealed ectopic expression of HOXB2 in15% of early PanIN lesions and 48 of 128 (38%) pancreatic cancer specimens. Expression of HOXB2 was associated with nonresectable tumors and was an independent predictor of poor survival in resected tumors. Conclusions: We identified aberrant expression of RA signaling components in pancreatic cancer, including HOXB2, which was expressed in a proportion of PanIN lesions. Ectopic expression of HOXB2 was associated with a poor prognosis for all patients with pancreatic cancer and was an independent predictor of survival in patients who underwent resection.Pancreatic cancer is the fifth leading cause of cancer death in Western societies with a 5-year survival rate of <10% (1). Pancreatic cancer presents at an advanced stage; thus, only 10% to 20% of patients are suitable for surgical treatment at the time of presentation (1). Clinical management of these patients is complicated by inconsistencies in the influence of conventional clinicopathologic variables on outcome suggesting that some of these variables lack accuracy. In addition, preoperative assessment of some variables such as lymph node metastases is difficult. Whereas in other cancers assessment of aberrations in gene expression that cosegregate with therapeutic response and outcome are being adopted routinely to increase predictive power (e.g., ER and HER-2/neu in breast cancer), there remain no molecular markers of clinical utility in pancreatic cancer. This highlights the need for the identification of novel regulatory pathways important in pancreatic cancer that may also have diagnostic, therapeutic and prognostic utility.There is now compelling histopathologic and molecular evidence to support the evolution of pancreatic cancer through a series of noninvasive duct...

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