For decades, retinoids and their synthetic derivatives have been well established anticancer treatments due to their ability to regulate cell growth and induce cell differentiation and apoptosis. Many studies have reported the promising role of retinoids in attaining better outcomes for adult or pediatric patients suffering from several types of cancer, especially acute myeloid leukemia and neuroblastoma. However, even this promising differentiation therapy has some limitations: retinoid toxicity and intrinsic or acquired resistance have been observed in many patients. Therefore, the identification of molecular markers that predict the therapeutic response to retinoid treatment is undoubtedly important for retinoid use in clinical practice. The purpose of this review is to summarize the current knowledge on candidate markers, including both genetic alterations and protein markers, for retinoid resistance and sensitivity in human malignancies.

Department of Pediatric Oncology University Hospital Brno and Faculty of Medicine Masaryk University Cernopolni 9 61300 Brno Czech Republic

International Clinical Research Center St Anne's University Hospital Pekarska 53 65691 Brno Czech Republic

Laboratory of Tumor Biology Department of Experimental Biology Faculty of Science Masaryk University Kotlarska 2 61137 Brno Czech Republic

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Nowak D, Stewart D, Koeffler HP. Differentiation therapy of leukemia: 3 decades of development. Blood. 2009;113:3655–3665. doi: 10.1182/blood-2009-01-198911. PubMed DOI PMC

Koeffler HP. Induction of differentiation of human acute myelogenous leukemia cells: therapeutic implications. Blood. 1983;62:709–721. PubMed

Dragnev KH, Rigas JR, Dmitrovsky E. The Retinoids and cancer prevention mechanisms. Oncologist. 2000;5:361–368. doi: 10.1634/theoncologist.5-5-361. PubMed DOI

Sakashita A, Kizaki M, Pakkala S, Schiller G, Tsuruoka N, Tomosaki R, et al. 9-cis-retinoic acid: effects on normal and leukemic hematopoiesis in vitro. Blood. 1993;81:1009–1016. PubMed

Khan AA, Villablanca JG, Reynolds CP, Avramis VI. Pharmacokinetic studies of 13-cis-retinoic acid in pediatric patients with neuroblastoma following bone marrow transplantation. Cancer Chemother Pharmacol. 1996;39:34–41. doi: 10.1007/s002800050535. PubMed DOI

Van Heusden J, Wouters W, Ramaekers FC, Krekels MD, Dillen L, Borgers M, et al. All-trans-retinoic acid metabolites significantly inhibit the proliferation of MCF-7 human breast cancer cells in vitro. Br J Cancer. 1998;77:26–32. doi: 10.1038/bjc.1998.5. PubMed DOI PMC

Reynolds CP. Differentiating agents in pediatric malignancies: Retinoids in neuroblastoma. Curr Oncol Rep. 2000;2:511–518. doi: 10.1007/s11912-000-0104-y. PubMed DOI

Hu J, Liu Y-F, Wu C-F, Xu F, Shen Z-X, Zhu Y-M, et al. Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2009;106:3342–3347. doi: 10.1073/pnas.0813280106. PubMed DOI PMC

Villablanca JG, Khan AA, Avramis VI, Seeger RC, Matthay KK, Ramsay NK, et al. Phase I trial of 13-cis-retinoic acid in children with neuroblastoma following bone marrow transplantation. J Clin Oncol. 1995;13:894–901. doi: 10.1200/JCO.1995.13.4.894. PubMed DOI

Mittal N, Malpani S, Dyson M, Ono M, Coon JS, Kim JJ, et al. Fenretinide: a novel treatment for endometrial cancer. PLoS One. 2014;9:e110410. doi: 10.1371/journal.pone.0110410. PubMed DOI PMC

Scarisbrick JJ, Morris S, Azurdia R, Illidge T, Parry E, Graham-Brown R, et al. U.K. consensus statement on safe clinical prescribing of bexarotene for patients with cutaneous T-cell lymphoma. Br J Dermatol. 2013;168:192–200. doi: 10.1111/bjd.12042. PubMed DOI

Murakami K, Sakukawa R, Sano M, Hashimoto A, Shibata J, Yamada Y, et al. Inhibition of angiogenesis and intrahepatic growth of colon cancer by TAC-101. Clin Cancer Res. 1999;5:2304–2310. PubMed

Klopper J, Kane M, Jimeno A, Sams S, French J, Pike L, et al. A phase II trial of Bexarotene for advanced differentiated thyroid cancer. Thyroid. 2015;25:563–564. doi: 10.1089/thy.2014.0399. PubMed DOI PMC

Chen J, Cao X, An Q, Zhang Y, Li K, Yao W, et al. Inhibition of cancer stem cell like cells by a synthetic retinoid. Nat Commun. 2018;9:1406. doi: 10.1038/s41467-018-03877-7. PubMed DOI PMC

Gigueere V. Retinoic acid receptors and cellular retinoid binding proteins: complex interplay in retinoid signaling. Endocr Rev. 1994;15:61–79. PubMed

Mongan NP, Gudas LJ. Diverse actions of retinoid receptors in cancer prevention and treatment. Differentiation. 2007;75:853–870. doi: 10.1111/j.1432-0436.2007.00206.x. PubMed DOI

Schug TT, Berry DC, Shaw NS, Travis SN, Noy N. Opposing effects of retinoic acid on cell growth result from alternate activation of two different nuclear receptors. Cell. 2007;129:723–733. doi: 10.1016/j.cell.2007.02.050. PubMed DOI PMC

Moise AR, Noy N, Palczewski K, Blaner WS. Delivery of retinoid-based therapies to target tissues. Biochemistry. 2007;46:4449–4458. doi: 10.1021/bi7003069. PubMed DOI PMC

Su M, Alonso S, Jones JW, Yu J, Kane MA, Jones RJ, et al. All-trans retinoic acid activity in acute myeloid leukemia: role of cytochrome P450 enzyme expression by the microenvironment. PLoS One. 2015;10:e0127790. doi: 10.1371/journal.pone.0127790. PubMed DOI PMC

Chlapek P, Slavikova V, Mazanek P, Sterba J, Veselska R. Why differentiation therapy sometimes fails: molecular mechanisms of resistance to Retinoids. Int J Mol Sci. 2018;19:132. doi: 10.3390/ijms19010132. PubMed DOI PMC

Belhabri A, Thomas X, Wattel E, Chelghoum Y, Anglaret B, Vekhoff A, et al. All trans retinoic acid in combination with intermediate-dose cytarabine and idarubicin in patients with relapsed or refractory non promyelocytic acute myeloid leukemia: a phase II randomized trial. Hematol J. 2002;3:49–55. doi: 10.1038/sj.thj.6200141. PubMed DOI

Milligan DW, Wheatley K, Littlewood T, Craig JIO, Burnett AK, NCRI Haematological Oncology Clinical Studies Group Fludarabine and cytosine are less effective than standard ADE chemotherapy in high-risk acute myeloid leukemia, and addition of G-CSF and ATRA are not beneficial: results of the MRC AML-HR randomized trial. Blood. 2006;107:4614–4622. doi: 10.1182/blood-2005-10-4202. PubMed DOI

Burnett AK, Russell NH, Hills RK, Bowen D, Kell J, Knapper S, et al. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2015;16:1295–1305. doi: 10.1016/S1470-2045(15)00193-X. PubMed DOI

Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, et al. Retinoic acid and arsenic trioxide for acute Promyelocytic leukemia 2013[WWW document] 2013. PubMed

Heuser M, Beutel G, Krauter J, Dohner K, von Neuhoff N, Schlegelberger B, et al. High meningioma 1 (MN1) expression as a predictor for poor outcome in acute myeloid leukemia with normal cytogenetics. Blood. 2006;108:3898–3905. doi: 10.1182/blood-2006-04-014845. PubMed DOI

Xiang L, Li M, Liu Y, Cen J, Chen Z, Zhen X, et al. The clinical characteristics and prognostic significance of MN1 gene and MN1-associated microRNA expression in adult patients with de novo acute myeloid leukemia. Ann Hematol. 2013;92:1063–1069. doi: 10.1007/s00277-013-1729-x. PubMed DOI

Shafik RE, Hassan NM, Meligui YME, Shafik HE. The meningioma 1 (MN1) gene is an independent poor prognostic factor in adult Egyptian acute myeloid leukemia patients. Asian Pac J Cancer Prev. 2017;18:609–613. PubMed PMC

Heuser M, Argiropoulos B, Kuchenbauer F, Yung E, Piper J, Fung S, et al. MN1 overexpression induces acute myeloid leukemia in mice and predicts ATRA resistance in patients with AML. Blood. 2007;110:1639–1647. doi: 10.1182/blood-2007-03-080523. PubMed DOI

van Wely KHM, Molijn AC, Buijs A, Meester-Smoor MA, Aarnoudse AJ, Hellemons A, et al. The MN1 oncoprotein synergizes with coactivators RAC3 and p300 in RAR-RXR-mediated transcription. Oncogene. 2003;22:699–709. doi: 10.1038/sj.onc.1206124. PubMed DOI

Warrell RP, de The H, Wang ZY, Degos L. Acute promyelocytic leukemia. N Engl J Med. 1993;329:177–189. doi: 10.1056/NEJM199307153290307. PubMed DOI

Rowley JD. Mapping of human chromosomal regions related to neoplasia: evidence from chromosomes 1 and 17. Proc Natl Acad Sci U S A. 1977;74:5729–5733. doi: 10.1073/pnas.74.12.5729. PubMed DOI PMC

de The H, Lavau C, Marchio A, Chomienne C, Degos L, Dejean A. The PML-RAR alpha fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell. 1991;66:675–684. doi: 10.1016/0092-8674(91)90113-D. PubMed DOI

Chen Z, Guidez F, Rousselot P, Agadir A, Chen SJ, Wang ZY, et al. PLZF-RAR alpha fusion proteins generated from the variant t(11;17)(q23;q21) translocation in acute promyelocytic leukemia inhibit ligand-dependent transactivation of wild-type retinoic acid receptors. Proc Natl Acad Sci U S A. 1994;91:1178–1182. doi: 10.1073/pnas.91.3.1178. PubMed DOI PMC

Redner RL, Rush EA, Faas S, Rudert WA, Corey SJ. The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion. Blood. 1996;87:882–886. PubMed

Wells RA, Catzavelos C, Kamel-Reid S. Fusion of retinoic acid receptor alpha to NuMA, the nuclear mitotic apparatus protein, by a variant translocation in acute promyelocytic leukaemia. Nat Genet. 1997;17:109–113. doi: 10.1038/ng0997-109. PubMed DOI

Arnould C, Philippe C, Bourdon V, Gregoire MJ, Berger R, Jonveaux P. The signal transducer and activator of transcription STAT5b gene is a new partner of retinoic acid receptor alpha in acute promyelocytic-like leukaemia. Hum Mol Genet. 1999;8:1741–1749. doi: 10.1093/hmg/8.9.1741. PubMed DOI

Catalano A, Dawson MA, Somana K, Opat S, Schwarer A, Campbell LJ, et al. The PRKAR1A gene is fused to RARA in a new variant acute promyelocytic leukemia. Blood. 2007;110:4073–4076. doi: 10.1182/blood-2007-06-095554. PubMed DOI

Yamamoto Y, Tsuzuki S, Tsuzuki M, Handa K, Inaguma Y, Emi N. BCOR as a novel fusion partner of retinoic acid receptor alpha in a t(X;17)(p11;q12) variant of acute promyelocytic leukemia. Blood. 2010;116:4274–4283. doi: 10.1182/blood-2010-01-264432. PubMed DOI

Yin CC, Jain N, Mehrotra M, Zhagn J, Protopopov A, Zuo Z, et al. Identification of a novel fusion gene, IRF2BP2-RARA, in acute promyelocytic leukemia. J Natl Compr Cancer Netw. 2015;13:19–22. doi: 10.6004/jnccn.2015.0005. PubMed DOI PMC

Chomienne C, Fenaux P, Degos L. Retinoid differentiation therapy in promyelocytic leukemia. FASEB J. 1996;10:1025–1030. doi: 10.1096/fasebj.10.9.8801163. PubMed DOI

Redner RL, Corey SJ, Rush EA. Differentiation of t(5;17) variant acute promyelocytic leukemic blasts by all-trans retinoic acid. Leukemia. 1997;11:1014–1016. doi: 10.1038/sj.leu.2400661. PubMed DOI

Licht JD, Chomienne C, Goy A, Chen A, Scott AA, Head DR, et al. Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11;17) Blood. 1995;85:1083–1094. PubMed

Strehl S, Konig M, Boztug H, Cooper BW, Suzukawa K, Zhang SJ, et al. All-trans retinoic acid and arsenic trioxide resistance of acute promyelocytic leukemia with the variant STAT5B-RARA fusion gene. Leukemia. 2013;27:1606–1610. doi: 10.1038/leu.2012.371. PubMed DOI

Shimomura Y, Mitsui H, Yamashita Y, Kamae T, Kanai A, Matsui H, et al. New variant of acute promyelocytic leukemia with IRF2BP2–RARA fusion. Cancer Sci. 2016;107:1165–1168. doi: 10.1111/cas.12970. PubMed DOI PMC

Langabeer SE, Preston L, Kelly J, Goodyer M, Elhassadi E, Hayat A. Molecular profiling: a case of ZBTB16-RARA acute promyelocytic leukemia. Case Rep Hematol. 2017;2017:7657393. PubMed PMC

Jovanovic JV, Rennie K, Culligan D, Peniket A, Lennard A, Harrison J, et al. Development of real-time quantitative polymerase chain reaction assays to track treatment response in retinoid resistant acute Promyelocytic leukemia. Front Oncol. 2011;1:35. doi: 10.3389/fonc.2011.00035. PubMed DOI PMC

De Angelis F, Breccia M. Molecular monitoring as a path to cure acute promyelocytic leukemia. Rare Cancers Ther. 2015;3:119–132. doi: 10.1007/s40487-015-0013-8. PubMed DOI PMC

Guidez F, Parks S, Wong H, Jovanovic JV, Mays A, Gilkes AF, et al. RARalpha-PLZF overcomes PLZF-mediated repression of CRABPI, contributing to retinoid resistance in t(11;17) acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2007;104:18694–18699. doi: 10.1073/pnas.0704433104. PubMed DOI PMC

Dolle P, Ruberte E, Leroy P, Morriss-Kay G, Chambon P. Retinoic acid receptors and cellular retinoid binding proteins. I A systematic study of their differential pattern of transcription during mouse organogenesis. Development. 1990;110:1133–1151. PubMed

Boylan JF, Gudas LJ. The level of CRABP-I expression influences the amounts and types of all-trans-retinoic acid metabolites in F9 teratocarcinoma stem cells. J Biol Chem. 1992;267:21486–21491. PubMed

Pfoertner S, Goelden U, Hansen W, Toepfer T, Geffers R, Ukena SN, et al. Cellular retinoic acid binding protein I: expression and functional influence in renal cell carcinoma. Tumour Biol. 2005;26:313–323. doi: 10.1159/000089262. PubMed DOI

Guidez F, Huang W, Tong JH, Dubois C, Balitrand N, Waxman S, et al. Poor response to all-trans retinoic acid therapy in a t(11;17) PLZF/RAR alpha patient. Leukemia. 1994;8:312–317. PubMed

Koken MH, Daniel MT, Gianni M, Zelent A, Licht J, Buzyn A, et al. Retinoic acid, but not arsenic trioxide, degrades the PLZF/RARalpha fusion protein, without inducing terminal differentiation or apoptosis, in a RA-therapy resistant t(11;17)(q23;q21) APL patient. Oncogene. 1999;18:1113–1118. doi: 10.1038/sj.onc.1202414. PubMed DOI

Petti MC, Fazi F, Gentile M, Diverio D, De Fabritiis P, De Propris MS, et al. Complete remission through blast cell differentiation in PLZF/RARalpha-positive acute promyelocytic leukemia: in vitro and in vivo studies. Blood. 2002;100:1065–1067. doi: 10.1182/blood-2001-12-0368. PubMed DOI

Girard N, Tremblay M, Humbert M, Grondin B, Haman A, Labrecque J, et al. RARα-PLZF oncogene inhibits C/EBPα function in myeloid cells. Proc Natl Acad Sci U S A. 2013;110:13522–13527. doi: 10.1073/pnas.1310067110. PubMed DOI PMC

Jiao B, Ren ZH, Liu P, Chen LJ, Shi JY, Dong Y, et al. 8-CPT-cAMP/all-trans retinoic acid targets t(11;17) acute promyelocytic leukemia through enhanced cell differentiation and PLZF/RARα degradation. Proc Natl Acad Sci U S A. 2013;110:3495–3500. doi: 10.1073/pnas.1222863110. PubMed DOI PMC

Tan Y, Bian S, Xu Z, Chen X, Qi X, Ren F, et al. The short isoform of the long-type PML-RARA fusion gene in acute promyelocytic leukaemia lacks sensitivity to all-trans-retinoic acid. Br J Haematol. 2013;162:93–97. doi: 10.1111/bjh.12362. PubMed DOI

Pandolfi PP, Alcalay M, Fagioli M, Zangrilli D, Mencarelli A, Diverio D, et al. Genomic variability and alternative splicing generate multiple PML/RAR alpha transcripts that encode aberrant PML proteins and PML/RAR alpha isoforms in acute promyelocytic leukaemia. EMBO J. 1992;11:1397–1407. doi: 10.1002/j.1460-2075.1992.tb05185.x. PubMed DOI PMC

Tong JH, Dong S, Geng JP, Huang W, Wang ZY, Sun GL, et al. Molecular rearrangements of the MYL gene in acute promyelocytic leukemia (APL, M3) define a breakpoint cluster region as well as some molecular variants. Oncogene. 1992;7:311–316. PubMed

Ruiz-Arguelles GJ, Garces-Eisele J, Reyes-Nunez V, Gomez-Rangel JD, Ruiz-Delgado GJ. More on geographic hematology: the breakpoint cluster regions of the PML/RARalpha fusion gene in Mexican mestizo patients with promyelocytic leukemia are different from those in Caucasians. Leuk Lymphoma. 2004;45:1365–1368. doi: 10.1080/10428190310001657344. PubMed DOI

Gu BW, Xiong H, Zhou Y, Chen B, Wang L, Dong S, et al. Variant-type PML-RAR(alpha) fusion transcript in acute promyelocytic leukemia: use of a cryptic coding sequence from intron 2 of the RAR(alpha) gene and identification of a new clinical subtype resistant to retinoic acid therapy. Proc Natl Acad Sci U S A. 2002;99:7640–7645. doi: 10.1073/pnas.112194799. PubMed DOI PMC

Bleul T, Ruhl R, Bulashevska S, Karakhanova S, Werner J, Bazhin AV. Reduced retinoids and retinoid receptors’ expression in pancreatic cancer: a link to patient survival. Mol Carcinog. 2015;54:870–879. doi: 10.1002/mc.22158. PubMed DOI

Mira-Y-Lopez R, Zheng WL, Kuppumbatti YS, Rexer B, Jing Y, Ong DE. Retinol conversion to retinoic acid is impaired in breast cancer cell lines relative to normal cells. J Cell Physiol. 2000;185:302–309. doi: 10.1002/1097-4652(200011)185:2<302::AID-JCP15>3.0.CO;2-#. PubMed DOI

El-Metwally TH, Hussein MR, Pour PM, Kuszynski CA, Adrian TE. High concentrations of retinoids induce differentiation and late apoptosis in pancreatic cancer cells in vitro. Cancer Biol Ther. 2005;4:602–611. doi: 10.4161/cbt.4.5.1762. PubMed DOI

Nakagawa T, Shimizu M, Shirakami Y, Tatebe H, Yasuda I, Tsurumi H, et al. Synergistic effects of acyclic retinoid and gemcitabine on growth inhibition in pancreatic cancer cells. Cancer Lett. 2009;273:250–256. doi: 10.1016/j.canlet.2008.08.004. PubMed DOI

Widschwendter M, Berger J, Daxenbichler G, Muller-Holzner E, Widschwendter A, Mayr A, et al. Loss of retinoic acid receptor beta expression in breast cancer and morphologically normal adjacent tissue but not in the normal breast tissue distant from the cancer. Cancer Res. 1997;57:4158–4161. PubMed

Picard E, Seguin C, Monhoven N, Rochette-Egly C, Siat J, Borrelly J, et al. Expression of retinoid receptor genes and proteins in non-small-cell lung cancer. J Natl Cancer Inst. 1999;91:1059–1066. doi: 10.1093/jnci/91.12.1059. PubMed DOI

Liu ZM, Ding F, Guo MZ, Zhang LY, Wu M, Liu ZH. Downregulation of retinoic acid receptor-β2 expression is linked to aberrant methylation in esophageal squamous cell carcinoma cell lines. World J Gastroenterol. 2004;10:771–775. doi: 10.3748/wjg.v10.i6.771. PubMed DOI PMC

Leelawat K, Ohuchida K, Mizumoto K, Mahidol C, Tanaka M. All-trans retinoic acid inhibits the cell proliferation but enhances the cell invasion through up-regulation of c-met in pancreatic cancer cells. Cancer Lett. 2005;224:303–310. doi: 10.1016/j.canlet.2004.10.016. PubMed DOI

Schug TT, Berry DC, Toshkov IA, Cheng L, Nikitin AY, Noy N. Overcoming retinoic acid-resistance of mammary carcinomas by diverting retinoic acid from PPARbeta/delta to RAR. Proc Natl Acad Sci U S A. 2008;105:7546–7551. doi: 10.1073/pnas.0709981105. PubMed DOI PMC

Gupta S, Pramanik D, Mukherjee R, Campbell NR, Elumalai S, de Wilde RF, et al. Molecular determinants of retinoic acid sensitivity in pancreatic cancer. Clin Cancer Res. 2012;18:280–289. doi: 10.1158/1078-0432.CCR-11-2165. PubMed DOI PMC

Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747–752. doi: 10.1038/35021093. PubMed DOI

Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98:10869–10874. doi: 10.1073/pnas.191367098. PubMed DOI PMC

Riggs BL, Hartmann LC. Selective estrogen-receptor modulators – mechanisms of action and application to clinical practice. New Engl J Med. 2003;348:618–629. doi: 10.1056/NEJMra022219. PubMed DOI

Fitzgerald P, Teng M, Chandraratna RA, Heyman RA, Allegretto EA. Retinoic acid receptor alpha expression correlates with retinoid-induced growth inhibition of human breast cancer cells regardless of estrogen receptor status. Cancer Res. 1997;57:2642–2650. PubMed

Schneider SM, Offterdinger M, Huber H, Grunt TW. Activation of retinoic acid receptor alpha is sufficient for full induction of retinoid responses in SK-BR-3 and T47D human breast cancer cells. Cancer Res. 2000;60:5479–5487. PubMed

Centritto F, Paroni G, Bolis M, Garattini SK, Kurosaki M, Barzago MM, et al. Cellular and molecular determinants of all-trans retinoic acid sensitivity in breast cancer: luminal phenotype and RARα expression. EMBO Mol Med. 2015;7:950–972. doi: 10.15252/emmm.201404670. PubMed DOI PMC

Swift ME, Wallden B, Wayner EA, Swisshelm K. Truncated RAR beta isoform enhances proliferation and retinoid resistance. J Cell Physiol. 2006;209:718–725. doi: 10.1002/jcp.20788. PubMed DOI

Tari AM, Lim SJ, Hung MC, Esteva FJ, Lopez-Berestein G. Her2/neu induces all-trans retinoic acid (ATRA) resistance in breast cancer cells. Oncogene. 2002;21:5224–5232. doi: 10.1038/sj.onc.1205660. PubMed DOI

Liu RZ, Graham K, Glubrecht DD, Germain DR, Mackey JR, Godbout R. Association of FABP5 expression with poor survival in triple-negative breast cancer. Am J Pathol. 2011;178:997–1008. doi: 10.1016/j.ajpath.2010.11.075. PubMed DOI PMC

Liu RZ, Garcia E, Glubrecht DD, Poon HY, Mackey JR, Godbout R. CRABP1 is associated with a poor prognosis in breast cancer: adding to the complexity of breast cancer cell response to retinoic acid. Mol Cancer. 2015;14:129. doi: 10.1186/s12943-015-0380-7. PubMed DOI PMC

Thulasiraman P, Garriga G, Danthuluri V, McAndrews DJ, Mohiuddin IQ. Activation of the CRABPII/RAR pathway by curcumin induces retinoic acid mediated apoptosis in retinoic acid resistant breast cancer cells. Oncol Rep. 2017;37:2007–2015. doi: 10.3892/or.2017.5495. PubMed DOI PMC

Carrier M, Joint M, Lutzing R, Page A, Rochette-Egly C. Phosphoproteome and transcriptome of RA-responsive and RA-resistant breast Cancer cell lines. PLoS One. 2016;11:e0157290. doi: 10.1371/journal.pone.0157290. PubMed DOI PMC

Masetti R, Biagi C, Zama D, Vendemini F, Martoni A, Morello W, et al. Retinoids in pediatric Onco-hematology: the model of acute promyelocytic leukemia and neuroblastoma. Adv Therapy. 2012;29:747–762. doi: 10.1007/s12325-012-0047-3. PubMed DOI

Peinemann F, van Dalen EC, Enk H, Berthold F. Retinoic acid postconsolidation therapy for high-risk neuroblastoma patients treated with autologous haematopoietic stem cell transplantation. Cochrane Database Syst Rev. 2017;8:CD010685. PubMed PMC

Schnabel CA, Selleri L, Cleary ML. Pbx1 is essential for adrenal development and urogenital differentiation. Genesis. 2003;37:123–130. doi: 10.1002/gene.10235. PubMed DOI

Thiaville MM, Stoeck A, Chen L, Wu R-C, Magnani L, Oidtman J, et al. Identification of PBX1 target genes in cancer cells by global mapping of PBX1 binding sites. PLoS One. 2012;7:e36054. doi: 10.1371/journal.pone.0036054. PubMed DOI PMC

Shah N, Wang J, Selich-Anderson J, Graham G, Siddiqui H, Li X, et al. PBX1 is a favorable prognostic biomarker as it modulates 13-cis retinoic acid-mediated differentiation in neuroblastoma. Clin Cancer Res. 2014;20:4400–4412. doi: 10.1158/1078-0432.CCR-13-1486. PubMed DOI PMC

Mao L, Ding J, Zha Y, Yang L, McCarthy BA, King W, et al. HOXC9 links cell-cycle exit and neuronal differentiation and is a prognostic marker in neuroblastoma. Cancer Res. 2011;71:4314–4324. doi: 10.1158/0008-5472.CAN-11-0051. PubMed DOI PMC

Tong J, Hannan F, Zhu Y, Bernards A, Zhong Y. Neurofibromin regulates G protein-stimulated adenylyl cyclase activity. Nat Neurosci. 2002;5:95–96. doi: 10.1038/nn792. PubMed DOI

Holzel M, Huang S, Koster J, Ora I, Lakeman A, Caron H, et al. NF1 is a tumor suppressor in neuroblastoma that determines retinoic acid response and disease outcome. Cell. 2010;142:218–229. doi: 10.1016/j.cell.2010.06.004. PubMed DOI PMC

Eleveld TF, Oldridge DA, Bernard V, Koster J, Daage LC, Diskin SJ, et al. Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations. Nat Genet. 2015;47:864–871. doi: 10.1038/ng.3333. PubMed DOI PMC

Mossé Yaël P., Maris John M. MEKing Retinoids Work Better. Cancer Cell. 2010;18(2):103–105. doi: 10.1016/j.ccr.2010.07.007. DOI

Fischer-Huchzermeyer Susan, Dombrowski Anna, Wilke Gordon, Stahn Verena, Streubel Anna, Mautner Victor Felix, Harder Anja. MEK inhibitors enhance therapeutic response towards ATRA in NF1 associated malignant peripheral nerve sheath tumors (MPNST) in-vitro. PLOS ONE. 2017;12(11):e0187700. doi: 10.1371/journal.pone.0187700. PubMed DOI PMC

Tallini Giovanni, Cin Paola Dal. HMGI(Y) and HMGI-C Dysregulation. Advances in Anatomic Pathology. 1999;6(5):237–246. doi: 10.1097/00125480-199909000-00001. PubMed DOI

Giannini G, Di Marcotullio L, Ristori E, Zani M, Crescenzi M, Scarpa S, et al. HMGI(Y) and HMGI-C genes are expressed in neuroblastoma cell lines and tumors and affect retinoic acid responsiveness. Cancer Res. 1999;59:2484–92. PubMed

CERIGNOLI F. HMGA Molecules in Neuroblastic Tumors. Annals of the New York Academy of Sciences. 2004;1028(1):122–132. doi: 10.1196/annals.1322.013. PubMed DOI

Barral José M., Bauer Christopher C., Ortiz Irving, Epstein Henry F. Unc-45Mutations inCaenorhabditis elegansImplicate a CRO1/She4p-like Domain in Myosin Assembly. The Journal of Cell Biology. 1998;143(5):1215–1225. doi: 10.1083/jcb.143.5.1215. PubMed DOI PMC

Chadli A., Graham J. D., Abel M. G., Jackson T. A., Gordon D. F., Wood W. M., Felts S. J., Horwitz K. B., Toft D. GCUNC-45 Is a Novel Regulator for the Progesterone Receptor/hsp90 Chaperoning Pathway. Molecular and Cellular Biology. 2006;26(5):1722–1730. doi: 10.1128/MCB.26.5.1722-1730.2006. PubMed DOI PMC

Epping M. T., Meijer L. A.T., Bos J. L., Bernards R. UNC45A Confers Resistance to Histone Deacetylase Inhibitors and Retinoic Acid. Molecular Cancer Research. 2009;7(11):1861–1870. doi: 10.1158/1541-7786.MCR-09-0187. PubMed DOI

Tassara M, Döhner K, Brossart P, Held G, Götze K, Horst H-A, et al. Valproic acid in combination with all-trans retinoic acid and intensive therapy for acute myeloid leukemia in older patients. Blood. 2014;123:4027–36. PubMed

Cowan Andrew J., Stevenson Phillip A., Gooley Ted A., Frayo Shani L., Oliveira George R., Smith Stephen D., Green Damian J., Roden Jennifer E., Pagel John M., Wood Brent L., Press Oliver W., Gopal Ajay K. Results of a phase I-II study of fenretinide and rituximab for patients with indolent B-cell lymphoma and mantle cell lymphoma. British Journal of Haematology. 2017;176(4):583–590. doi: 10.1111/bjh.14451. PubMed DOI PMC

Toma S, Raffo P, Nicolo G, Canavese G, Margallo E, Vecchio C, et al. Biological activity of all-trans-retinoic acid with and without tamoxifen and alpha-interferon 2a in breast cancer patients. Int J Oncol. 2000;17:991–1000. PubMed

Basu Partha, Jenson Alfred Bennett, Majhi Tapas, Choudhury Prabir, Mandal Ranajit, Banerjee Dipanwita, Biswas Jaydip, Pan Jianmin, Rai Shesh Nath, Ghim Shin je, Miller Donald. Phase 2 Randomized Controlled Trial of Radiation Therapy Plus Concurrent Interferon-Alpha and Retinoic Acid Versus Cisplatin for Stage III Cervical Carcinoma. International Journal of Radiation Oncology*Biology*Physics. 2016;94(1):102–110. doi: 10.1016/j.ijrobp.2015.09.040. PubMed DOI

Duvic Madeleine, Hymes Kenneth, Heald Peter, Breneman Debra, Martin Ann G., Myskowski Patricia, Crowley Connie, Yocum Richard C. Bexarotene Is Effective and Safe for Treatment of Refractory Advanced-Stage Cutaneous T-Cell Lymphoma: Multinational Phase II-III Trial Results. Journal of Clinical Oncology. 2001;19(9):2456–2471. doi: 10.1200/JCO.2001.19.9.2456. PubMed DOI

Children’s Oncology Group (CCG 09709), Villablanca JG, Krailo MD, Ames MM, Reid JM, Reaman GH, et al. Phase I trial of oral fenretinide in children with high-risk solid tumors: a report from the Children’s Oncology Group (CCG 09709). J Clin Oncol. 2006;24:3423–30. PubMed

Zapletalova D., André N., Deak L., Kyr M., Bajciova V., Mudry P., Dubska L., Demlova R., Pavelka Z., Zitterbart K., Skotakova J., Husek K., Martincekova A., Mazanek P., Kepak T., Doubek M., Kutnikova L., Valik D., Sterba J. Metronomic Chemotherapy with the COMBAT Regimen in Advanced Pediatric Malignancies: A Multicenter Experience. Oncology. 2012;82(5):249–260. doi: 10.1159/000336483. PubMed DOI

Penas-Prado Marta, Hess Kenneth R., Fisch Michael J., Lagrone Lore W., Groves Morris D., Levin Victor A., De Groot John F., Puduvalli Vinay K., Colman Howard, Volas-Redd Gena, Giglio Pierre, Conrad Charles A., Salacz Michael E., Floyd Justin D., Loghin Monica E., Hsu Sigmund H., Gonzalez Javier, Chang Eric L., Woo Shiao Y., Mahajan Anita, Aldape Kenneth D., Yung W. K. Alfred, Gilbert Mark R. Randomized phase II adjuvant factorial study of dose-dense temozolomide alone and in combination with isotretinoin, celecoxib, and/or thalidomide for glioblastoma. Neuro-Oncology. 2014;17(2):266–273. doi: 10.1093/neuonc/nou155. PubMed DOI PMC

High-Dose Chemotherapy Plus Autologous Stem Cell Transplantation Compared With Intermediate-Dose Chemotherapy Plus Autologous Stem Cell Transplantation With or Without Isotretinoin in Treating Young Patients With Recurrent High-Grade Gliomas - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT00078988.

Puduvalli Vinay K., Yung W.K. Alfred, Hess Kenneth R., Kuhn John G., Groves Morris D., Levin Victor A., Zwiebel James, Chang Susan M., Cloughesy Timothy F., Junck Larry, Wen Patrick, Lieberman Frank, Conrad Charles A., Gilbert Mark R., Meyers Christina A., Liu Vivien, Mehta Minesh P., Nicholas M. Kelly, Prados Michael. Phase II Study of Fenretinide (NSC 374551) in Adults With Recurrent Malignant Gliomas: A North American Brain Tumor Consortium Study. Journal of Clinical Oncology. 2004;22(21):4282–4289. doi: 10.1200/JCO.2004.09.096. PubMed DOI PMC

Muto Yasutoshi, Moriwaki Hisataka, Ninomiya Mitsuo, Adachi Sadashi, Saito Akiko, Takasaki Ken Takeshi, Tanaka Takuji, Tsurumi Kaito, Okuno Masataka, Tomita Eiichi, Nakamura Toshiyuki, Kojima Takao. Prevention of Second Primary Tumors by an Acyclic Retinoid, Polyprenoic Acid, in Patients with Hepatocellular Carcinoma. New England Journal of Medicine. 1996;334(24):1561–1568. doi: 10.1056/NEJM199606133342402. PubMed DOI

Nijhof I S, Groen R W J, Lokhorst H M, van Kessel B, Bloem A C, van Velzen J, de Jong-Korlaar R, Yuan H, Noort W A, Klein S K, Martens A C M, Doshi P, Sasser K, Mutis T, van de Donk N W C J. Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab. Leukemia. 2015;29(10):2039–2049. doi: 10.1038/leu.2015.123. PubMed DOI

Arrieta O, González-De la Rosa CH, Aréchaga-Ocampo E, Villanueva-Rodríguez G, Cerón-Lizárraga TL, Martínez-Barrera L, et al. Randomized phase II trial of All-trans-retinoic acid with chemotherapy based on paclitaxel and cisplatin as first-line treatment in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2010;28:3463–71. PubMed

Reynolds CP, Frgala T, Tsao-Wei DD, Groshen S, Morgan R, McNamara M, et al. High plasma levels of fenretinide (4-HPR) were associated with improved outcome in a phase II study of recurrent ovarian cancer: A study by the California Cancer Consortium. JCO. 2007;25(18_suppl):5555.

Stromal TARgeting for PAncreatic Cancer (STAR_PAC) - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03307148.

BRAF V600E and Redifferentiation Therapy in Radioiodine-refractory Papillary Thyroid Cancer - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03363347.

Moore M. M., Stockler M., Lim R., Mok T. S. K., Millward M., Boyer M. J. A phase II study of fenretinide in patients with hormone refractory prostate cancer: a trial of the Cancer Therapeutics Research Group. Cancer Chemotherapy and Pharmacology. 2010;66(5):845–850. doi: 10.1007/s00280-009-1228-x. PubMed DOI

Vaishampayan Ulka, Heilbrun Lance K., Parchment Ralph E., Jain Vikash, Zwiebel James, Boinpally Ramesh R., LoRusso Patricia, Hussain Maha. Phase II trial of fenretinide in advanced renal carcinoma. Investigational New Drugs. 2005;23(2):179–185. doi: 10.1007/s10637-005-5864-7. PubMed DOI

Schneider Bryan J., Worden Francis P., Gadgeel Shirish M., Parchment Ralph E., Hodges Collette M., Zwiebel James, Dunn Rodney L., Wozniak Antoinette J., Kraut Michael J., Kalemkerian Gregory P. Phase II trial of fenretinide (NSC 374551) in patients with recurrent small cell lung cancer. Investigational New Drugs. 2009;27(6):571–578. doi: 10.1007/s10637-009-9228-6. PubMed DOI

LIPPMAN SCOTT M. Treatment of Advanced Squamous Cell Carcinoma of the Skin with Isotretinoin. Annals of Internal Medicine. 1987;107(4):499. doi: 10.7326/0003-4819-107-4-499. PubMed DOI

Phase II Study Of Roferon and Accutane For Patients With T-Cell Malignancies - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT00038376.

Hiller B, Bradtke J, Balz H, Rieder H. CyDAS Online Analysis Site. 2004. http://www.cydas.org/OnlineAnalysis/. Accessed 2 Feb 2018.

The Role of ATRA, Natural Ligand of Retinoic Acid Receptors, on EMT-Related Proteins in Breast Cancer: Minireview

Comparative Analysis of Putative Prognostic and Predictive Markers in Neuroblastomas: High Expression of PBX1 Is Associated With a Poor Response to Induction Therapy

Prediction of neuroblastoma cell response to treatment with natural or synthetic retinoids using selected protein biomarkers