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TNFα is a pleiotropic cytokine which fuels tumor cell growth, invasion, and metastasis in some malignancies, while in others it induces cytotoxic cell death. However, the molecular mechanism by which TNFα exerts its diverse effects on breast cancer subtypes remains elusive. Using in vitro assays and mouse xenografts, we show here that TNFα contributes to the aggressive properties of triple negative breast cancer (TNBC) cell lines via upregulation of TNFAIP3(A20). In a striking contrast, TNFα induces a potent cytotoxic cell death in luminal (ER+) breast cancer cell lines which fail to upregulate A20 expression. Overexpression of A20 not only protects luminal breast cancer cell lines from TNFα-induced cell death via inducing HSP70-mediated anti-apoptotic pathway but also promotes a robust EMT/CSC phenotype by activating the pStat3-mediated inflammatory signaling. Furthermore, A20 overexpression in luminal breast cancer cells induces aggressive metastatic properties in mouse xenografts via generating a permissive inflammatory microenvironment constituted by granulocytic-MDSCs. Collectively, our results reveal a mechanism by which A20 mediates pleiotropic effects of TNFα playing role in aggressive behaviors of TNBC subtype while its deficiency results in TNFα-induced apoptotic cell death in luminal breast cancer subtype.

Our study involves inhibition of glycolysis and inhibition of the HER2 pathway, which is highly expressed in many types of cancer. Decreased survival, negative metastasis, and induced apoptosis are expected due to the combined inhibition of these two targets. Trastuzumab was used as the HER2 inhibitor and lonidamine was used as the HK2 inhibitor. Lonidamine (LND) was delivered to cells as hybrid nanoparticles to enhance the effect of lonidamine and make it target specific. Separate cytotoxicity studies were conducted for LND, LND‐NP and Tmab. While application of lonidamine alone gave an IC50 value of 124.6 μM, application in NP reduced the IC50 value to 44.18 μM. In addition, the combination of Tmab and LND‐NP showed synergistic effects compared to treatments alone in other analyses. On the aspect of apoptosis, this combination showed a 14‐fold increased apoptosis compared to the control group. This combination therapy can prevent drug resistance. In addition, the hybrid nanoparticle structure used will prevent the formation of toxicity as it will ensure that LND is administered to the body with less repetition. Our study aims to minimize the negative effects of the chemotherapy process by improving it with various variations in future studies. [ABSTRACT FROM AUTHOR]