title: Leptin receptor maintains cancer stem-like properties in triple negative breast cancer cells.
abstract: Despite new therapies, breast cancer continues to be the second leading cause of cancer mortality in women, a consequence of recurrence and metastasis. In recent years, a population of cancer cells has been identified, called cancer stem cells (CSCs) with self-renewal capacity, proposed to underlie tumor recurrence and metastasis. We previously showed that the adipose tissue cytokine LEPTIN, increased in obesity, promotes the survival of CSCs in vivo. Here, we tested the hypothesis that the leptin receptor (LEPR), expressed in mammary cancer cells, is necessary for maintaining CSC-like and metastatic properties. We silenced LEPR via shRNA lentivirus transduction and determined that the expression of stem cell self-renewal transcription factors NANOG, SOX2, and OCT4 (POU5F1) is inhibited. LEPR-NANOG signaling pathway is conserved between species because we can rescue NANOG expression in human LEPR-silenced cells with the mouse LepR. Using a NANOG promoter GFP reporter, we showed that LEPR is enriched in NANOG promoter active (GFP+) cells. In lineage tracing studies, we showed that the GFP+ cells divide in a symmetric and asymmetric manner. LEPR-silenced MDA-MB-231 cells exhibit a mesenchymal to epithelial transition morphologically, increased E-CADHERIN and decreased VIMENTIN expression compared with control cells. Finally, LEPR-silenced cells exhibit reduced cell proliferation, self-renewal in tumor sphere assays, and tumor outgrowth in xenotransplant studies. Given the emergence of NANOG as a pro-carcinogenic protein in multiple cancers, these studies suggest that inhibition of LEPR may be a promising therapeutic approach to inhibit NANOG and thereby neutralize CSC functions.
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, NC10, Cleveland, Ohio 44195, USA Department of Nutritional Sciences, The University of Texas, Austin, Texas, USA Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas, USA Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA ImageIQ, Cleveland, Ohio, USA Case Comprehensive Cancer Center, Cleveland, Ohio, USA.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Zheng
authors.forename: Lauren
authors.initials: L
authors.lastname: Banaszak
authors.forename: Sarah
authors.initials: S
authors.lastname: Fracci
authors.forename: Diana
authors.initials: D
authors.lastname: Basali
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Dunlap
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Hursting
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.forename: Anita B
authors.initials: AB
authors.lastname: Hjlemeland
authors.forename: Amit
authors.initials: A
authors.lastname: Vasanji
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Berger
authors.forename: Justin D
authors.initials: JD
authors.lastname: Lathia
authors.forename: Ofer
authors.initials: O
authors.lastname: Reizes
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000071317:Nanog Homeobox Protein; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D054411:Receptors, Leptin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C515448:LEPR protein, human; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D054411:Receptors, Leptin; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse
keywords: NANOG; breast cancer; cancer stem cell; leptin receptor; obesity
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