Tumor necrosis factor receptor signaling modulates carcinogenesis in a mouse model of breast cancer.

Abstract

Pro-inflammatory conditions have long been associated with mammary carcinogenesis and breast cancer progression. The underlying mechanisms are incompletely understood but signaling of pro-inflammatory cytokine TNFα through its receptors TNFR1 and TNFR2 is a major mediator of inflammation in both obesity and in the response of tissues to radiation, 2 known risk factors for the development of breast cancer. Here, we demonstrated the loss of one TNFR2 allele led to ductal hyperplasia in the mammary gland with increased numbers of mammary epithelial stem cell and terminal end buds. Furthermore, loss of one TNFR2 allele increased the incidence of breast cancer in MMTV-Wnt1 mice and resulted in tumors with a more aggressive phenotype and metastatic potential. The underlying mechanisms include a preferential activation of canonical NF-κB signaling pathway and autocrine production of TNFα. Analysis of the TCGA dataset indicated inferior overall survival for patients with down-regulated TNFR2 expression. These findings unravel the imbalances in TNFR signaling promote the development and progression of breast cancer, indicating that selective agonists of TNFR2 could potentially modulate the risk for breast cancer in high-risk populations.

• Authors: Ling He, Kruttika Bhat, Sara Duhacheck-Muggy, Angeliki Ioannidis, Le Zhang, Nhan T Nguyen, Neda A Moatamed, Frank Pajonk
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 23 Issue 2 Pg. 197-209 (02 2021) ISSN: 1476-5586 [Electronic] United States
• PMID: 33383310 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers
• Cytokines
• NF-kappa B
• Receptors, Tumor Necrosis Factor
• Receptors, Tumor Necrosis Factor, Type II

Topics

• Alleles
• Animals
• Biomarkers
• Breast Neoplasms (etiology, metabolism, pathology)
• Cell Line, Tumor
• Cell Transformation, Neoplastic (genetics, metabolism)
• Cytokines (metabolism)
• Disease Models, Animal
• Disease Susceptibility
• Female
• Humans
• Immunohistochemistry
• Mice
• Mice, Knockout
• NF-kappa B (metabolism)
• Organogenesis (genetics)
• Proteomics (methods)
• Receptors, Tumor Necrosis Factor (genetics, metabolism)
• Receptors, Tumor Necrosis Factor, Type II (genetics, metabolism)
• Signal Transduction