The contradictory functions of NLRX1 in breast cancer allow for suppression or promotion of tumor growth and metastasis in a cell-specific manner.

Abstract

Abstract Breast cancer is a deadly malignancy that is responsible for 15% of all cancer-related deaths in women. Examining the innate immune system in breast cancer has revealed the importance of pattern recognition receptors, such as NLRX1, in disease progression. NLRX1 has been implicated as a tumor suppressor because it suppresses inflammation by many mechanisms, including by inhibiting the NF-κB pathway. Here, we investigated the potential of NLRX1 as a tumor suppressor in breast cancer when it is expressed either by healthy host cells or cancer cells. To determine the role of NLRX1 in healthy host cells, we used the 4T1 breast cancer model in WT and Nlrx1−/− (KO) mice. KO mice exhibited increased lung metastasis and tumor size compared to WT mice. Gene expression data revealed increased expression of proliferation, survival, growth, invasion, and metastatic genes in tumors from KO mice compared to WT mice. Thus, NLRX1 in healthy host cells is protective against breast cancer tumor growth and metastasis. Next, we investigated the role of NLRX1 in breast cancer cells. 4T1 cells were transduced to overexpress NLRX1 and injected into WT (WTOE) and KO(KOOE) mice. Transduction controls were also generated and injected into WT (WTOE-CTL) and KO (KOOE-CTL) mice. KOOE mice developed larger tumors than KOOE-CTL mice. KOOE mice also developed more lung metastasis compared to WTOE, WTOE-CTL, and KOOE-CTL mice. This suggests NLRX1 in breast cancer cells contributes to tumor growth and metastasis, which directly contradicts the function of NLRX1 in healthy host cells and demonstrates a cell-specific function of NLRX1 in breast cancer. These cell-specific differences are critical foundations for the development of NLR-based breast cancer therapies.