TNFalpha up-regulates SLUG via the NF-kappaB/HIF1alpha axis, which imparts breast cancer cells with a stem cell-like phenotype

Gianluca Storci, Pasquale Sansone, Sara Mari, Gabriele D'Uva, Simona Tavolari, Tiziana Guarnieri, Mario Taffurelli, Claudio Ceccarelli, Donatella Santini, Pasquale Chieco, Kenneth B. Marcu, Massimiliano Bonafè

Research output: Contribution to journalArticle

93 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)682-691
Number of pages10
JournalJournal of Cellular Physiology
Volume225
Issue number3
DOIs
Publication statusPublished - Dec 2010

Fingerprint

NF-kappa B
Stem cells
Up-Regulation
Stem Cells
Tumor Necrosis Factor-alpha
Cells
Breast Neoplasms
Phenotype
Tumors
Inflammation Mediators
Estrogen Receptor alpha
Gene expression
Epithelial-Mesenchymal Transition
Neoplastic Stem Cells
Transcriptome
Cytokines
Extracellular Matrix
Neoplasms
Down-Regulation
Carcinoma

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

TNFalpha up-regulates SLUG via the NF-kappaB/HIF1alpha axis, which imparts breast cancer cells with a stem cell-like phenotype. / Storci, Gianluca; Sansone, Pasquale; Mari, Sara; D'Uva, Gabriele; Tavolari, Simona; Guarnieri, Tiziana; Taffurelli, Mario; Ceccarelli, Claudio; Santini, Donatella; Chieco, Pasquale; Marcu, Kenneth B.; Bonafè, Massimiliano.

In: Journal of Cellular Physiology, Vol. 225, No. 3, 12.2010, p. 682-691.

Research output: Contribution to journalArticle

Storci, G, Sansone, P, Mari, S, D'Uva, G, Tavolari, S, Guarnieri, T, Taffurelli, M, Ceccarelli, C, Santini, D, Chieco, P, Marcu, KB & Bonafè, M 2010, 'TNFalpha up-regulates SLUG via the NF-kappaB/HIF1alpha axis, which imparts breast cancer cells with a stem cell-like phenotype', Journal of Cellular Physiology, vol. 225, no. 3, pp. 682-691. https://doi.org/10.1002/jcp.22264
Storci, Gianluca ; Sansone, Pasquale ; Mari, Sara ; D'Uva, Gabriele ; Tavolari, Simona ; Guarnieri, Tiziana ; Taffurelli, Mario ; Ceccarelli, Claudio ; Santini, Donatella ; Chieco, Pasquale ; Marcu, Kenneth B. ; Bonafè, Massimiliano. / TNFalpha up-regulates SLUG via the NF-kappaB/HIF1alpha axis, which imparts breast cancer cells with a stem cell-like phenotype. In: Journal of Cellular Physiology. 2010 ; Vol. 225, No. 3. pp. 682-691.
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