Overcoming retinoic acid-resistance of mammary carcinomas by diverting retinoic acid from PPARβ/δ to RAR

Retinoic acid (RA) displays potent anticarcinogenic activities that are mediated by the nuclear retinoic acid receptors (RARs). However, use of RA in oncology is limited by RA resistance acquired during carcinogenesis. Moreover, in some cancers, RA facilitates rather than inhibits growth. A clue to...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 105; no. 21; pp. 7546 - 7551
Main Authors Schug, Thaddeus T, Berry, Daniel C, Toshkov, Illia A, Cheng, Le, Nikitin, Alexander Yu, Noy, Noa
Format Journal Article
LanguageEnglish
Published National Academy of Sciences 27.05.2008
National Acad Sciences
Subjects
Apoptosis
Biological Sciences
Cancer
Carrier proteins
Cell growth
Cell lines
Epithelial cells
Messenger RNA
Mice
Receptors
Tumors
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Summary:Retinoic acid (RA) displays potent anticarcinogenic activities that are mediated by the nuclear retinoic acid receptors (RARs). However, use of RA in oncology is limited by RA resistance acquired during carcinogenesis. Moreover, in some cancers, RA facilitates rather than inhibits growth. A clue to this paradoxical behavior was recently suggested by the findings that RA also activates PPARβ/δ, a receptor involved in mitogenic and anti-apoptotic activities. The observations that partitioning of RA between its two receptors is regulated by two intracellular lipid-binding proteins--CRABP-II, which targets RA to RAR, and FABP5, which delivers it to PPARβ/δ--further suggest that RA resistance may stem from the deregulation of the binding proteins, resulting in activation of PPARβ/δ rather than RAR. Here, we show that, in the RA-resistant mouse model of breast cancer MMTV-neu, RA indeed activates the nonclassical RA receptor PPARβ/δ. This behavior was traced to an aberrantly high intratumor FABP5/CRABP-II ratio. Decreasing this ratio in mammary tissue diverted RA from PPARβ/δ to RAR and suppressed tumor growth. The data demonstrate the existence of a mechanism that underlies RA resistance in tumors, indicate that CRABP-II functions as a tumor suppressor, and suggest that the inhibition of FABP5 may comprise a therapeutic strategy for overcoming RA resistance in some tumors.
Bibliography:Author contributions: T.T.S. and D.C.B. contributed equally to this work; A.Y.N. and N.N. designed research; T.T.S., D.C.B., I.A.T., and L.C. performed research; T.T.S., D.C.B., I.A.T., A.Y.N., and N.N. analyzed data; and T.T.S., D.C.B., I.A.T., A.Y.N., and N.N. wrote the paper.
Edited by Keith R. Yamamoto, University of California, San Francisco, CA, and approved March 28, 2008
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0709981105