Tumor Necrosis Factor Receptor Signaling Modulates Carcinogenesis in a Mouse Model of Breast Cancer

Proinflammatory conditions have long been associated with mammary carcinogenesis and breast cancer progression. The underlying mechanisms are incompletely understood but signaling of TNFα through its receptors TNFR1 and TNFR2 is a major mediator of inflammation in both, obesity and in the response of tissues to radiation, two known risk factors for the development of breast cancer. Using the MMTV-Wnt1 mouse model for spontaneous breast cancer and knockout mice for TNFR1 and TNFR2 we report that loss of a TNFR2 allele leads to ductal hyperplasia in the mammary gland with increased numbers of mammary epithelial stem cell and terminal endbuds. Furthermore, that loss of one TNFR2 allele increases the incidence of breast cancers in MMTV-Wnt1 mice and results in tumors with a more aggressive phenotype and metastatic potential. The underlying mechanisms include a preferential activation of canonical NF-κB signaling pathways and autocrine production of TNFα. Analysis of the TCGA dataset indicated inferior overall survival for patients with down-regulated TNFR2 expression. We conclude, that 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. Significance Statement Over the past four decades the treatment results for patients suffering from breast cancer have constantly improved, leaving breast cancer prevention as an important frontier against the second leading cause of cancer death in the United States. Obesity has become a national health crisis and is a known proinflammatory risk factor for breast cancer. Our study describes a previously unknown aspect of proinflammatory signaling on breast cancer development and progression, thus suggesting novel potential targets to modulate the incidence of the disease.