Electrophilic Nitroalkenes Inhibit Triple Negative Breast Cancer Metastasis

Abstract

Triple negative breast cancer (TNBC), which lacks estrogen receptor (ER), progesterone receptor (PR) and Her2/Neu, is an aggressive and therapy‐resistant metastatic cancer. A high level of tumor necrosis factor‐α (TNFα) expression and activation in TNBC patients is associated with distant tumor metastasis. Current therapy for TNBC is limited, and there is an unmet need for novel therapeutic agents. Electrophilic fatty acid nitroalkenes are endogenous signaling mediators that modulate cell differentiation and proliferation via post‐translational modification (PTM) of functionally‐significant nucleophilic amino acids (Cys, His) of transcriptional regulatory proteins such as NFκB, PPARγ, and Keap1/Nrf2. Recent studies have revealed that an exemplary electrophilic nitroalkene, nitro‐oleic acid (NO2‐OA), inhibits TNFα‐induced TNBC cell migration. NFκB plays an important role in tumor development and progression, and its signaling actions are constitutively activated in ER‐negative breast cancer cell lines and primary tumors. Notably, NO2‐OA causes polyubiquitination and degradation of NFκB RelA protein via protein nitroalkylation in TNBC cells. Therefore, it is hypothesized that electrophilic nitroalkenes have therapeutic potential that inhibit TNBC metastasis through down‐regulation of TNFα‐NFκB signaling. We demonstrate that NO2‐OA significantly inhibits two TNFα‐induced NFκB‐regulated genes involved in tumor metastasis, ICAM‐1 and uPA, in TNBC cells. The TNBC xenograft study indicates that NO2‐OA reduces MDA‐MB‐231 tumor xenograft growth. Baseline mortality rate for vehicle treated mice was 28.6 percent due to metastasis phenotype. We show that the survival curve increased with NO2‐OA dose level, correlating with better survival of TNBC xenograft mice. Moreover, ICAM‐1 and uPA expression levels in NO2‐OA treated tumors are lower compared to vehicle treated tumors. This study serves as a prelude to the clinical study of electrophilic nitroalkenes as therapeutic agents that may display high selectivity for inhibition of TNBC progression and metastasis.