C/EBPβ stabilizes oxidative stress in triple-negative breast cancer cells, driving taxane resistance and immune evasion.

Triple-negative breast cancer (TNBC) is a form of breast cancer clarified by low expression of estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2). For this reason, therapeutics aimed at targeting these receptors are ineffective in cases of TNBC, which leads to a poorer prognosis. Consequently, there is a need for novel therapeutics at targeting this subtype. CCAAT/enhancer-binding protein β (C/EBPβ) is a leucine zipper transcription factor with a traditional function in mammary gland development and macrophage differentiation. In tumors, C/EBPβ is associated with metastatic and chemoresistant forms of breast cancer. Previous efforts at targeting this transcription factor in the tumor have been hampered by off-target effects and low penetrance into the intratumoral space. Furthermore, studies into C/EBPβ knockdown in vitro have been mixed, owing in part to two distinct isoforms that are differentially expressed in healthy and cancerous tissues. Given that the function of C/EBPβ is closely tied to hypoxia factors such as hypoxia-inducible factor-1α, we hypothesized that the hypoxic intratumoral space may be driving specific isoform development and consequently the pro-metastatic phenotype observed clinically. To this end, we have developed an aptamer-small interfering RNA (siRNA) conjugate containing a transferrin receptor 1 (TfR1) aptamer (a receptor activated under hypoxic conditions) linked to a C/EBPβ siRNA. We have measured C/EBPβ's suppression of metastasis in traditional cell culture under hypoxic conditions and in vivo. These results point toward a novel approach to the contradictory role of C/EBPβ as a driver and mediator of metastasis and a potential therapeutic for its treatment.