Molecular determinants of retinoic acid sensitivity in pancreatic cancer.
OBJECTIVE
To identify a predictive molecular "signature" for sensitivity to retinoic acid in pancreatic cancer.


METHODS
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-trans retinoic acid (ATRA). Cell proliferation, apoptosis, and migration/invasion assays were used to measure the in vitro response. Tumor growth was monitored in subcutaneous xenografts in athymic nude mice for 4 weeks.


RESULTS
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(high)CRABP2(null) cells could be circumvented by ectopic expression of CRABP2. Alternatively, reexpression of endogenous CRABP2 could be enabled in FABP5(high)CRABP2(null) PDAC lines by exposure to decitabine and trichostatin A, thereby relieving epigenetic silencing of the CRABP2 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.


CONCLUSIONS
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.
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Sonal
S
Gupta
Dipankar
D
Pramanik
Radha
R
Mukherjee
Nathaniel R
NR
Campbell
Sathyanarayanan
S
Elumalai
Roeland F
RF
de Wilde
Seung-Mo
SM
Hong
Michael G
MG
Goggins
Ana
A
De Jesus-Acosta
Daniel
D
Laheru
Anirban
A
Maitra
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C493412:FABP5 protein, human; D050556:Fatty Acid-Binding Proteins; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; C082928:retinoic acid binding protein II, cellular; D014212:Tretinoin