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

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

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

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    Storci, G., Sansone, P., Mari, S., D'Uva, G., Tavolari, S., Guarnieri, T., Taffurelli, M., Ceccarelli, C., Santini, D., Chieco, P., Marcu, K. B., & 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, 225(3), 682-691. https://doi.org/10.1002/jcp.22264