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Expression of HOXB2, a Retinoic Acid Signalingtarget in Pancreatic Cancer and Pancreatic Intraepithelial Neoplasia Davendra Segara,1Andrew V

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Expression of HOXB2, a Retinoic Acid Signalingtarget in Pancreatic Cancer and Pancreatic Intraepithelial Neoplasia Davendra Segara,1Andrew V Cancer Prevention Expression of HOXB2, a Retinoic Acid SignalingTarget in Pancreatic Cancer and Pancreatic Intraepithelial Neoplasia Davendra Segara,1Andrew V. Biankin,1, 2 James G. Kench,1, 3 Catherine C. Langusch,1Amanda C. Dawson,1 David A. Skalicky,1David C. Gotley,4 Maxwell J. Coleman,2 Robert L. Sutherland,1and Susan M. Henshall1 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 oligo- nucleotide 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 toAffymetrix Genechip HG-U133 oligonucleotide microarrays. A relational database integrating data from publicly available resources was created toidentify candidate genes potentially relevant topancreatic 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,andHOXB2),manyof which are known to be aberrantly expressed in pancreatic cancer and PanIN. HOXB2, a down- stream target of RA, was up-regulated 6.7-fold in pancreatic cancer compared with normal pan- creas. Immunohistochemistry revealed ectopic expression of HOXB2 in15% of early PanINlesions 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 that some of these variables lack accuracy. In addition, in Western societies with a 5-year survival rate of <10% (1). preoperative assessment of some variables such as lymph node Pancreatic cancer presents at an advanced stage; thus, only metastases is difficult. Whereas in other cancers assessment of 10% to 20% of patients are suitable for surgical treatment at aberrations in gene expression that cosegregate with therapeu- the time of presentation (1). Clinical management of these tic response and outcome are being adopted routinely to patients is complicated by inconsistencies in the influence of increase predictive power (e.g., ER and HER-2/neu in breast conventional clinicopathologic variables on outcome suggesting 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 Authors’ Affiliations: 1Cancer Research Program, Garvan Institute of Medical pancreatic cancer that may also have diagnostic, therapeutic Research and 2Division of Surgery, St. Vincent’s Hospital, Darlinghurst, Sydney, and prognostic utility. New South Wales, Australia; 3Institute of Clinical Pathology and Medical Research, There is now compelling histopathologic and molecular 4 Westmead Hospital, Westmead, New South Wales, Australia; and University of evidence to support the evolution of pancreatic cancer through Queensland, Department of Surgery, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia a series of noninvasive duct lesions called pancreatic intra- Received 9/5/04; revised 2/1/05; accepted 2/10/05. epithelial neoplasia (PanIN; refs. 2, 3). Early duct lesions Grant support: Royal Australasian College of Surgeons, National Health and designated PanIN-1A and PanIN-1B show minimal cytologic Medical Research Council of Australia, St. Vincent’s Clinic Foundation Sydney, and architectural atypia and are associated with activating K-ras Cancer Council New South Wales, R.T. Hall Trust, and Prostate Cancer Foundation mutations (4), shortened telomeres (5), and overexpress of Australia (S.M. Henshall). WAF1/CIP1 The costs of publication of this article were defrayed in part by the payment of page p21 (6). PanIN-2 lesions exhibit mild to moderate charges. This article must therefore be hereby marked advertisement in accordance cytologic and architectural atypia and are associated with with 18 U.S.C. Section 1734 solely to indicate this fact. loss of p16INK4A expression (7) and cyclin D1 overexpression Note: D. Segara and A. Biankin contributed equally to this work. (6). PanIN-3 exhibits significant cytologic and architectural Requests for reprints: Robert L. Sutherland, Cancer Research Program Garvan atypia, manifests p53 mutations (8), and loss of DPC4/ 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: Smad4 expression (6). These molecular aberrations increase [email protected]. in frequency with advancing PanIN lesions through to invasive F 2005 American Association for Cancer Research. cancer. www.aacrjournals.org3587 Clin Cancer Res 2005;11(9) May 1, 2005 Downloaded from clincancerres.aacrjournals.org on October 9, 2021. © 2005 American Association for Cancer Research. Cancer Prevention During vertebrate development, retinoic acid (RA) signaling clinicopathologic data. Multiple samples of pancreatic tissue of f500 is important for the correct patterning of embryonic structures mg were excised intraoperatively from 12 patients, undergoing (9). Endodermal expression of pdx-1 (a homeobox-containing pancreatic resection for pancreatic cancer, immediately snap frozen in j transcription factor essential for pancreatic development) is liquid nitrogen and stored at À80 C, before RNA extraction. Total RNA was isolated from 12 pancreatic cancer specimens and six macroscopi- induced by RA (10) and marks a pluripotent population of cells cally and microscopically normal appearing pancreas from the same that give rise to all cell types in the pancreas. RA signaling patients (matched). Biotinylated cRNA for Affymetrix Genechip hybrid- regulates pancreas exocrine lineage selection, and treatment ization was prepared through a single round of reverse transcription with RA analogues can effect a shift from an acinar to a ductal with Superscript II (Life Technologies, Rockville, MD) followed by se- phenotype through epithelial-mesenchymal interactions (11). cond strand synthesis to create double stranded cDNA. After purification Such a shift from an exocrine to a predominantly ductal the cDNA was transcribed and labeled using a T7 polymerase (Enzo phenotype is characteristic of mouse models of pancreatic Technologies, New York, NY) and purified (27). Hybridization cocktails cancer development. In addition, pancreatic stellate cells, which were prepared as per the Affymetrix protocol (Affymetrix, Santa Clara, are essential for the development of fibrosis associated with CA) and quality assured on Affymetrix Test3 arrays, before hybridization chronic pancreatitis and pancreatic cancer, store retinoids in fat to HG-U133A and B oligonucleotide microarrays. Data analysis. A relational database was constructed using File- droplets, and in turn can have their function altered with RA Maker Pro (FileMaker, Inc., San Francisco, CA) to facilitate multiple analogue treatment in vitro (12). The retinoid signal is queries of gene expression data generated from the above experiments transduced by two families of nuclear transcription factors: and public domain data available electronically from the Internet. The RA receptors (RAR) and retinoid X receptors, that are members database incorporated (a) transcript profiles of pancreatic cancer and of the nuclear receptor superfamily, which in the presence of normal pancreas from the experiments done in this study (absolute ligand heterodimerize to activate the transcription of target values); (b) mathematical algorithms programmed within the database genes through RA response elements (13). Although few RA to generate fold change comparisons between the average expression response elements have been identified, one of the mechanisms across all samples of pancreatic cancer to the average in normal pancreas; by which retinoids exert their effects is thought to be through (c) linear statistical analyses generated using the Affymetrix Data Mining regulation of HOX gene expression (9, 14). Tool Software (MAS 5.0), which included t test and Mann-Whitney U Homeobox genes are transcription factors with established test data for comparisons between normal pancreas and pancreatic cancer and (d) interactive molecular pathway maps were generated using roles in development and cell function. The homeobox is a GenMAPP software (Gladstone Institutes UCSF, San Francisco, CA, highly conserved 183-bp DNA sequence coding for a 61-amino- http://www.GenMAPP.org/default.html), designed to incorporate tran- acid domain, the homeodomain (15). This region binds DNA script profile data into maps of known pathways including those elements, primarily those that contain a TAAT core motif involved in carcinogenesis and development. Data files using Swissprot (16). Accordingly, homeodomain containing
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