Kruppel-like factor 2 suppresses mammary carcinoma growth by regulating retinoic acid signaling
Metrics: PDF 1006 views | HTML 1259 views | ?
Wei Zhang1, Liraz Levi1, Pallab Banerjee2,*, Mukesh Jain3 and Noa Noy1,4
1 Department of Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
2 Dana-Farber Cancer Institute, Boston, Massachusetts, USA
3 The Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
4 Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
* is deceased
Noa Noy, email:
Keywords: Kruppel-like factor, nuclear receptors, retinoic acid, vitamin A, breast cancer
Received: August 07, 2015 Accepted: September 12, 2015 Published: September 21, 2015
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.