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

Authors' Affiliations: ¹ Cancer Research Program, Garvan Institute of Medical Research and ² Division of Surgery, St. Vincent's Hospital, Darlinghurst, Sydney, New South Wales, Australia;³ Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, New South Wales, Australia; and ⁴ University of Queensland, Department of Surgery, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia

Requests for reprints: Robert L. Sutherland, Cancer Research Program Garvan Institute of Medical Research 384 Victoria Street, Darlinghurst. New South Wales 2010, Australia. Phone: 61-2-9295-8322; Fax: 61-2-9295-8321; E-mail: r.sutherland{at}garvan.org.au.

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 (RAR, 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 in 15% 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.

Key Words: molecular markers • pancreatic cancer • molecular profiling • retinoic acid • HOXB2 prognosis

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