The S100A7-c-Jun activation domain binding protein 1 pathway enhances prosurvival pathways in breast cancer.
S100A7 is among the most highly expressed genes in preinvasive breast cancer, is a marker of poor survival when expressed in invasive disease, and promotes breast tumor progression in experimental models. To explore the mechanism of action, we examined the role of S100A7 in cell survival and found that overexpression of S100A7 in MDA-MB-231 cell lines promotes survival under conditions of anchorage-independent growth. This effect is paralleled by increased activity of nuclear factor-kappaB (3-fold) and phospho-Akt (4-fold), which are known to mediate prosurvival pathways. S100A7 and phospho-Akt are also correlated in breast tumors examined by immunohistochemistry (n = 142; P < 0.0001; r = 0.34). To explore the underlying mechanism, we examined the role of a putative c-Jun activation domain-binding protein 1 (Jab1)-binding domain within S100A7 using a panel of MDA-MB-231 breast cell lines stably transfected with either S100A7 or S100A7 mutated at the Jab1 domain. Structural analysis by three-dimensional protein modeling, immunoprecipitation, and yeast two-hybrid assay and functional analysis using transfected reporter gene and Western blot assays revealed that the in vitro effects of S100A7 on phospho-Akt and the nuclear factor-kappaB pathway are dependent on the Jab1-binding site and the interaction with Jab1. Enhanced epidermal growth factor receptor signaling was also found to correlate with the increased phospho-Akt. Furthermore, the Jab1-binding domain is also necessary for the enhanced tumorigenicity conferred by S100A7 expression in murine xenograft tumors in vivo. We conclude that the S100A7-Jab1 pathway acts to enhance survival under conditions of cellular stress, such as anoikis, which may promote progression of breast cancer.
Department of Biochemistry and Medical Genetics, University of Manitoba, Canada.
Ethan D
ED
Emberley
Yulian
Y
Niu
Linda
L
Curtis
Sandra
S
Troup
Sanat K
SK
Mandal
Jeffery N
JN
Myers
Spencer B
SB
Gibson
Leigh C
LC
Murphy
Peter H
PH
Watson
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000075686:COP9 Signalosome Complex; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D009368:Neoplasm Transplantation; D010447:Peptide Hydrolases / Q000378:metabolism / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014183:Transplantation, Heterologous
D000075686:COP9 Signalosome Complex; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D010447:Peptide Hydrolases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins; D014157:Transcription Factors; C089242:S100A7 protein, human; C494918:AKT1 protein, human; C501488:COPS5 protein, human; C501490:Cops5 protein, mouse