TNFalpha up-regulates SLUG via the NF-kappaB/HIF1alpha axis, which imparts breast cancer cells with a stem cell-like phenotype.
Extracellular and intracellular mediators of inflammation, such as tumor necrosis factor alpha (TNFα) and NF-kappaB (NF-κB), play major roles in breast cancer pathogenesis, progression and relapse. SLUG, a mediator of the epithelial-mesenchymal transition process, is over-expressed in CD44(+)/CD24(-) tumor initiating breast cancer cells and in basal-like carcinoma, a subtype of aggressive breast cancer endowed with a stem cell-like gene expression profile. Cancer stem cells also over-express members of the pro-inflammatory NF-κB network, but their functional relationship with SLUG expression in breast cancer cells remains unclear. Here, we show that TNFα treatment of human breast cancer cells up-regulates SLUG with a dependency on canonical NF-κB/HIF1α signaling, which is strongly enhanced by p53 inactivation. Moreover, SLUG up-regulation engenders breast cancer cells with stem cell-like properties including enhanced expression of CD44 and Jagged-1 in conjunction with estrogen receptor alpha down-regulation, growth as mammospheres, and extracellular matrix invasiveness. Our results reveal a molecular mechanism whereby TNFα, a major pro-inflammatory cytokine, imparts breast cancer cells with stem cell-like features, which are connected to increased tumor aggressiveness.
Center for Applied Biomedical Research (CRBA), St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
Gianluca
G
Storci
Pasquale
P
Sansone
Sara
S
Mari
Gabriele
G
D'Uva
Simona
S
Tavolari
Tiziana
T
Guarnieri
Mario
M
Taffurelli
Claudio
C
Ceccarelli
Donatella
D
Santini
Pasquale
P
Chieco
Kenneth B
KB
Marcu
Massimiliano
M
Bonafè
D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D034622:RNA Interference; D011994:Recombinant Proteins / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D018874:Spheroids, Cellular; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
C497483:CD44 protein, human; D002135:Calcium-Binding Proteins; D047628:Estrogen Receptor alpha; C497442:HIF1A protein, human; D018960:Hyaluronan Receptors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D016328:NF-kappa B; D011994:Recombinant Proteins; C000604407:SNAI1 protein, human; D000072099:Serrate-Jagged Proteins; D000071250:Snail Family Transcription Factors; C495901:TP53 protein, human; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53