MLK4 kinase regulates the DNA damage response and promotes triple-negative breast cancer chemoresistance

Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by the absence of estrogen and progesterone receptors, and the lack of HER2 amplification or overexpression. Chemoresistance is currently one of the major challenges in the treatment TNBC. Therefore, there is a need towards identification of the novel molecular targets that could be exploited to overcome TNBC chemoresistance. In this study, we found that knock-down of Mixed-Lineage Kinase 4 (MLK4), a member of MAP3K family of serine/threonine kinases, sensitizes TNBC cell to chemotherapy and impairs activation of DNA repair pathways upon genotoxic treatment. DNA damage response signaling network coordinates transcriptional response at multiple levels to preserve cellular homeostasis and promote survival in response to genotoxic stress. Since MLK4-deficient cells were compromised for DNA damage response signaling activation following doxorubicin treatment, we hypothesized that the loss of MLK4 could significantly affect global transcriptomic changes induced by chemotherapy in TNBC cells. To test this hypothesis we performed gene expression profiling by mRNA-seq in HCC1806 TNBC cells transfected with control or MLK4-targeting siRNAs and treated with either 1 μM of doxorubicin for 24 h or vehicle only (DMSO control). Our RNA-seq analysis revealed that MLK4 is required for DNA damage-induced expression of several NF-кB-associated cytokines, including IL-6, which facilitates TNBC cells survival in an autocrine manner. mRNA-seq data from HCC1806 TNBC cell line transfected with MLK4-targeting (siMLK4) or control (siNT) siRNA, and treated with doxorubicin or vehicle only (DMSO) for 24h