Abstract

<div>Abstract<p><b>Purpose:</b> To identify a predictive molecular “signature” for sensitivity to retinoic acid in pancreatic cancer.</p><p><b>Experimental Design:</b> Fourteen patient-derived, low-passage pancreatic ductal adenocarcinoma (PDAC) lines with varied expression of fatty acid–binding protein 5 (FABP5) and cellular retinoic acid–binding protein 2 (CRABP2) were used to evaluate the response to all-<i>trans</i> retinoic acid (ATRA). Cell proliferation, apoptosis, and migration/invasion assays were used to measure the <i>in vitro</i> response. Tumor growth was monitored in subcutaneous xenografts in athymic nude mice for 4 weeks.</p><p><b>Results:</b> Response to ATRA was observed to be dependent upon differential expression of FABP5 versus CRABP2. Thus, elevated FABP5 expression was associated with minimal cytotoxicity and tumor growth inhibition and a paradoxical increase in migration and invasion. Conversely, CRABP2 expression in the absence of FABP5 was associated with significant tumor growth inhibition with ATRA, even in gemcitabine-resistant tumors. The ATRA-resistant phenotype of FABP5<sup>high</sup>CRABP2<sup>null</sup> cells could be circumvented by ectopic expression of <i>CRABP2</i>. Alternatively, reexpression of endogenous CRABP2 could be enabled in FABP5<sup>high</sup>CRABP2<sup>null</sup> PDAC lines by exposure to decitabine and trichostatin A, thereby relieving epigenetic silencing of the <i>CRABP2</i> gene promoter. Immunohistochemical staining for FABP5 in archival human tissue microarrays identifies a subset of cases (13 of 63, ∼20%) which are negative for FABP5 expression and might be candidates for ATRA therapy.</p><p><b>Conclusions:</b> The widely used agent ATRA deserves a “second look” in PDAC, but needs to be targeted to patient subsets with biopsy-proven FABP5-negative tumors, or be combined with a chromatin-modifying agent to reexpress endogenous CRABP2. <i>Clin Cancer Res; 18(1); 280–9. ©2011 AACR</i>.</p></div>

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