title: GD3 synthase regulates epithelial-mesenchymal transition and metastasis in breast cancer.
abstract: The epithelial-mesenchymal transition (EMT) bestows cancer cells with increased stem cell properties and metastatic potential. To date, multiple extracellular stimuli and transcription factors have been shown to regulate EMT. Many of them are not druggable and therefore it is necessary to identify targets, which can be inhibited using small molecules to prevent metastasis. Recently, we identified the ganglioside GD2 as a novel breast cancer stem cell marker. Moreover, we found that GD3 synthase (GD3S)--an enzyme involved in GD2 biosynthesis--is critical for GD2 production and could serve as a potential druggable target for inhibiting tumor initiation and metastasis. Indeed, there is a small molecule known as triptolide that has been shown to inhibit GD3S function. Accordingly, in this manuscript, we demonstrate that the inhibition of GD3S using small hairpin RNA or triptolide compromises the initiation and maintenance of EMT instigated by various signaling pathways, including Snail, Twist and transforming growth factor-β1 as well as the mesenchymal characteristics of claudin-low breast cancer cell lines (SUM159 and MDA-MB-231). Moreover, GD3S is necessary for wound healing, migration, invasion and stem cell properties in vitro. Most importantly, inhibition of GD3S in vivo prevents metastasis in experimental as well as in spontaneous syngeneic wild-type mouse models. We also demonstrate that the transcription factor FOXC2, a central downstream effector of several EMT pathways, directly regulates GD3S expression by binding to its promoter. In clinical specimens, the expression of GD3S correlates with poor prognosis in triple-negative human breast tumors. Moreover, GD3S expression correlates with activation of the c-Met signaling pathway leading to increased stem cell properties and metastatic competence. Collectively, these findings suggest that the GD3S-c-Met axis could serve as an effective target for the treatment of metastatic breast cancers.
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: T R
authors.initials: TR
authors.lastname: Sarkar
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: V L
authors.initials: VL
authors.lastname: Battula
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Werden
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: G V
authors.initials: GV
authors.lastname: Vijay
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: E Q
authors.initials: EQ
authors.lastname: Ramirez-Peña
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Taube
authors.affiliation: Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Chang
authors.affiliation: Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Miura
authors.affiliation: Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, USA.
authors.forename: W
authors.initials: W
authors.lastname: Porter
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: N
authors.initials: N
authors.lastname: Sphyris
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Andreeff
authors.affiliation: 1] Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA [2] Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA [3] Center for Stem Cells and Developmental Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: S A
authors.identifier: 0000000259184276
authors.initials: SA
authors.lastname: Mani
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D004852:Epoxy Compounds / Q000494:pharmacology; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental; D010616:Phenanthrenes / Q000494:pharmacology*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology*; D012799:Sialyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004224:Diterpenes; D004852:Epoxy Compounds; D051858:Forkhead Transcription Factors; D010616:Phenanthrenes; D034741:RNA, Small Interfering; C082078:mesenchyme fork head 1 protein; C001899:triptolide; D012799:Sialyltransferases; C043662:alpha-N-acetylneuraminate alpha-2,8-sialyltransferase; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
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