Overcoming retinoic acid-resistance of mammary carcinomas by diverting retinoic acid from PPARβ/δ to RAR
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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.
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RA binding activates the nuclear translocation of FABP5, which then delivers the ligand to the PPARβ/δ subtype (but not to the other PPARs).
“Most interestingly, RA binding activates the nuclear translocation of FABP5, which then delivers the ligand to the PPAR  / ␦ subtype (but not to the other PPARs) (21)(22)(23).”
From Vitamin A and retinoid signaling: genomic and nongenomic effects (2013) · cites this paper as [22]
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- Authors
- Schug, T. T., Berry, D. C., Toshkov, I. A., Cheng, L., Nikitin, A. Y., & Noy, N.
- Affiliations
- Cornell University (US)
- Case Western Reserve University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-05-27
- Volume
- 105
- Issue
- 21
- Pages
- 7546-7551
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2396692
- OpenAlex
- W2093995222
- Cited by
- 172
- References
- 45
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 9 · 2023: 5 · 2022: 7 · 2021: 10 · 2020: 8 · 2019: 9 · 2018: 10 · 2017: 12 · 2016: 12 · 2015: 15 · 2014: 15 · 2013: 10 · 2012: 7
- FWCI
- 5.35
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (CA107013)
- National Cancer Institute (R01CA096823, R01 CA 96823, R01CA107013, T32CA009682)
- National Center for Research Resources (CA96823, K26RR017595)
- Institute of Genetics
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- retinoic acid resistance, PPARδ, retinoic acid receptor, breast cancer, FABP5, CRABP2, lipid-binding proteins, tumor suppressor, retinoic acid signaling, breast cancer treatment
- MeSH terms
- Animals, Antineoplastic Agents, Carcinoma, Disease Models, Animal, Mice, Transgenic, Neoplasm Proteins, Transcription, Genetic, Tretinoin, Mammary Neoplasms, Animal, Receptors, Retinoic Acid, Drug Resistance, Neoplasm, Cell Line, Tumor, PPAR delta, PPAR-beta, Fatty Acid-Binding Proteins, Mice
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