title: Gadd45a functions as a promoter or suppressor of breast cancer dependent on the oncogenic stress.
abstract: Gadd45a plays a pivotal role as a stress sensor that modulates cellular responses to various stress stimuli including oncogenic stress. We reported that the stress sensor Gadd45a gene functions as a tumor suppressor in Ras-driven breast tumorigenesis via increasing JNK-mediated apoptosis and p38-mediated senescence. In contrast, here, we show that Gadd45a promotes Myc-driven breast cancer by negatively regulating MMP10 via GSK3 β/β-catenin signaling, resulting in increased tumor vascularization and growth. These novel findings indicate that Gadd45a functions as either tumor promoter or suppressor, is dependent on the oncogenic stress, and is mediated via distinct signaling pathways. Collectively, these novel findings highlight the significance of the type of oncogenic alteration on how stress response genes function during initiation and progression of tumorigenesis. Because Gadd45a is a target for BRCA1 and p53, these findings have implications regarding BRCA1/p53 tumor suppressor functions.
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, Pennsylvania, USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Tront
authors.forename: Yajue
authors.initials: Y
authors.lastname: Huang
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Fornace
authors.forename: Albert A
authors.initials: AA
authors.lastname: Fornace
authors.forename: Barbara
authors.initials: B
authors.lastname: Hoffman
authors.forename: Dan A
authors.initials: DA
authors.lastname: Liebermann
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc / Q000235:genetics / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007150:Immunohistochemistry; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053506:Matrix Metalloproteinase 10 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D034622:RNA Interference; D015398:Signal Transduction; D047368:Tumor Burden; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism; D000097642:GADD45 Proteins
chemical_list: D018797:Cell Cycle Proteins; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D053506:Matrix Metalloproteinase 10; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins