title: Kruppel-like factor 2 suppresses mammary carcinoma growth by regulating retinoic acid signaling.
abstract: The transcription factor Kruppel-like factor 2 (KLF2) displays anticarcinogenic activities but the mechanism that underlies this activity is unknown. We show here that KLF2 is markedly downregulated in human breast cancers and that its expression positively correlates with breast cancer patient survival. We show further that KLF2 suppresses tumor development by controlling the transcriptional activity of the vitamin A metabolite retinoic acid (RA). RA regulates gene transcription by activating two types of nuclear receptors: RA receptors (RARs), which inhibit tumor development, and peroxisome proliferator-activated receptor β/δ (PPARβ/δ), which promotes tumorigenesis. The partitioning of RA between these receptors is regulated by two carrier proteins: cellular retinoic acid-binding protein 2 (CRABP2), which delivers RA to RARs, and fatty acid-binding protein 5 (FABP5), which shuttles ligands to PPARβ/δ. We show that KLF2 induces the expression of CRABP2 and RARγ and inhibits the expression FABP5 and PPARβ/δ thereby shifting RA signaling from the pro-carcinogenic FABP5/PPARβ/δ to the growth-suppressing CRABP2/RAR path. The data thus reveal that KLF2 suppresses tumor growth by controlling the transcriptional activities of RA.
authors.affiliation: Department of Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
authors.forename: Liraz
authors.initials: L
authors.lastname: Levi
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Pallab
authors.initials: P
authors.lastname: Banerjee
authors.affiliation: The Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Mukesh
authors.initials: M
authors.lastname: Jain
authors.affiliation: Department of Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.|Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Noa
authors.initials: N
authors.lastname: Noy
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D015536:Down-Regulation; D050556:Fatty Acid-Binding Proteins / Q000037:antagonists & inhibitors; D005260:Female; D064593:Heterografts; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D014158:Transcription, Genetic; D014212:Tretinoin / Q000378:metabolism*; D000097768:Retinoic Acid Receptor gamma
chemical_list: D050556:Fatty Acid-Binding Proteins; D051741:Kruppel-Like Transcription Factors; D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C493412:FABP5 protein, human; C096161:KLF2 protein, human; C082928:retinoic acid binding protein II, cellular
keywords: Kruppel-like factor; breast cancer; nuclear receptors; retinoic acid; vitamin A