Cooperative Pathways Regulating Metastasis: The Inflammatory Cytokine Tumor Necrosis Factor α Brings the Evil Out of Rasα

Breast cancer is a multi-factorial disease in which interactions between tumor microenvironment (TME) and tumor cells dictate disease development and progression.

In this study we determined the relative contribution of inflammatory cytokines highly expressed in TME of breast cancer patients, tumor necrosis factor α (TNFα) and interleukin 1b (IL-1β), vs. intrinsic oncogenic alterations in Ras and p53 to malignant processes of the breast.

To this end, we used two model systems. In the first model of non-transformed cells we found that oncogenic RasG12V could not induce expression of pro-cancerous chemokine cluster in the absence of cooperation with down-regulated p53 activities, and that TNFα and IL-1β had a stronger effect on the acquisition of the malignancy phenotype than alterations in the intrinsic cellular components.

In the second model of breast tumor cells we found that in contrast to the non-transformed cells, RasG12V induced the pro-malignant angiogenic chemokine CXCL8 without need for accompanying down-regulation of p53. Moreover, TNFα and IL-1b synergized with RasG12V, together amplifying CXCL8 expression. WT-Ras, which is the prevalent form of Ras in breast cancer patients, was not active in promoting CXCL8; however, TNFα stimulation turned WT-Ras into an active and oncogenic entity and the joint activities of TNFα+WT-Ras have led via MEK activation to increased CXCL8 release. The additive effects of TNFα+Ras, mediated by NF-kB and AP-1, increased angiogenesis and elevated dissemination of tumor cells to lymph nodes.

Overall, our findings propose that in breast cancer patients, where TME is enriched with TNFα, the cytokine may rescue the oncogenic potential of WT-Ras, together leading to a more aggressive disease. These findings shed light on novel therapeutic strategy targeting TME to treat breast cancer patients.