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 - Tập 225 Số 3 - Trang 682-691 - 2010
Gianluca Storci1, Pasquale Sansone2, Sara Mari1, Gabriele D’Uva3, Simona Tavolari4, Tiziana Guarnieri4, Mario Taffurelli5, Claudio Ceccarelli6, Donatella Santini6, Pasquale Chieco1, Kenneth B. Marcu1,7, Massimiliano Bonafè8
1Center for Applied Biomedical Research (CRBA), St Orsola‐Malpighi Hospital, University of Bologna, Bologna, Italy
2Department of Pharmacology and Toxicology, University of Bologna, Bologna, Italy
3Department of Biochemistry, University of Bologna, Bologna, Italy
4Department of Experimental Evolutionary Biology, University of Bologna, Bologna, Italy
5Department of Surgical and Anesthesiological Sciences, University of Bologna. Bologna, Italy
6Department of Gastroenterology and Pathology, University of Bologna, Bologna, Italy
7Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York
8Department of Experimental Pathology, University of Bologna, Bologna, Italy

Tóm tắt

AbstractExtracellular 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. J. Cell. Physiol. 225: 682–691, 2010. © 2010 Wiley‐Liss, Inc.

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Journal of Cellular Physiology

Tập 225 Số 3

682-691

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