The pleiotropic effects of TNFα in breast cancer subtypes is regulated by TNFAIP3/A20.

Abstract

TNFα is a pleiotropic cytokine which fuels tumor cell growth, invasion, and metastasis in some malignancies, while in others it induces cytotoxic cell death. However, the molecular mechanism by which TNFα exerts its diverse effects on breast cancer subtypes remains elusive. Using in vitro assays and mouse xenografts, we show here that TNFα contributes to the aggressive properties of triple negative breast cancer (TNBC) cell lines via upregulation of TNFAIP3(A20). In a striking contrast, TNFα induces a potent cytotoxic cell death in luminal (ER+) breast cancer cell lines which fail to upregulate A20 expression. Overexpression of A20 not only protects luminal breast cancer cell lines from TNFα-induced cell death via inducing HSP70-mediated anti-apoptotic pathway but also promotes a robust EMT/CSC phenotype by activating the pStat3-mediated inflammatory signaling. Furthermore, A20 overexpression in luminal breast cancer cells induces aggressive metastatic properties in mouse xenografts via generating a permissive inflammatory microenvironment constituted by granulocytic-MDSCs. Collectively, our results reveal a mechanism by which A20 mediates pleiotropic effects of TNFα playing role in aggressive behaviors of TNBC subtype while its deficiency results in TNFα-induced apoptotic cell death in luminal breast cancer subtype.

• Authors: Eunmi Lee, Maria Ouzounova, Raziye Piranlioglu, Minh Thu Ma, Mustafa Guzel, Daniela Marasco, Ahmed Chadli, Jason E Gestwicki, John K Cowell, Max S Wicha, Khaled A Hassan, Hasan Korkaya
• Journal: Oncogene (Oncogene) Vol. 38 Issue 4 Pg. 469-482 (01 2019) ISSN: 1476-5594 [Electronic] England
• PMID: 30166590 (Publication Type: Journal Article)

Chemical References

• HSP72 Heat-Shock Proteins
• Neoplasm Proteins
• Purine Nucleosides
• RNA, Neoplasm
• Recombinant Fusion Proteins
• STAT3 Transcription Factor
• STAT3 protein, human
• Tumor Necrosis Factor-alpha
• VER 155008
• TNFAIP3 protein, human
• Tumor Necrosis Factor alpha-Induced Protein 3

Topics

• Animals
• Apoptosis (physiology)
• Breast Neoplasms (genetics, metabolism, pathology)
• Cell Line, Tumor
• Epithelial-Mesenchymal Transition
• Female
• Gene Expression Regulation, Neoplastic
• Genetic Pleiotropy
• HSP72 Heat-Shock Proteins (antagonists & inhibitors, physiology)
• Heterografts
• Humans
• Inflammation
• Lung Neoplasms (secondary)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Neoplasm Invasiveness (genetics)
• Neoplasm Proteins (genetics, physiology)
• Neoplastic Stem Cells (metabolism, pathology)
• Purine Nucleosides (pharmacology)
• RNA, Neoplasm (biosynthesis, genetics)
• Recombinant Fusion Proteins (metabolism, pharmacology)
• STAT3 Transcription Factor (physiology)
• Signal Transduction
• Triple Negative Breast Neoplasms (genetics, metabolism, pathology)
• Tumor Necrosis Factor alpha-Induced Protein 3 (biosynthesis, genetics, physiology)
• Tumor Necrosis Factor-alpha (genetics, physiology)