Year: 2017
Type: conference-abstract
Abstract: Patients with breast cancer brain metastases (BCBM) suffer from a devastating outcome despite recent progress in a variety of therapeutic modalities. Triple-negative breast cancer (TNBC) and human epidermal growth factor receptor HER-2 positive breast cancer are the two major breast cancer (BC) subtypes that have a higher risk for developing brain metastases compared to Hormone Receptor-positive subtypes. The mechanisms by which the disseminated tumor cells overcome the multistep defense mechanism in the brain, adapt the microenvironment, and subsequently initiate metastasis foci remain elusive. Mixed lineage kinase 4 (MLK4) is a poorly characterized serine/threonine kinase, which we recently identified as a key molecule for initiation of mesenchymal glioblastoma through activation of the NF-kB signaling. In this study, we sought to determine the expression and function of MLK4 in the process of initiation of BCBM. Through analysis of The Cancer Genome Atlas (TCGA) breast cancer exon sequencing data sets, MLK4 was found to be highly expressed in TNBC in comparison to other subtypes. Staining of human BC & BCBM tissues as well showed relatively higher MLK4 expression in TNBC. Expression profiling revealed that TNBC cells exhibit higher MLK4 expression after being primed with Human brain endothelial cells secretory factors. Silencing MLK4 significantly reduced in vitro colony formation ability as well as in vivo brain metastatic capabilities of TNBC cells, while this effect was not evident after direct injection of TNBC cells into the mouse brain, suggesting that MLK4 is required for the transmigration of disseminated BC cells towards brain parenchyma to initiate brain metastases. For the therapeutic development purpose, we performed the structure-based drug design, leading to identification of a small molecule inhibitor of MLK4. We will test its activity on a set of patient-derived breast cancer cells in vitro and their xenografted tumor mouse models in vivo.
Source: Neuro-Oncology
Authors: Heba Allah Alsheikh, Mutsuko Minata, Shinobu Yamaguchi, Shuko Harada, Deniz Peker, Rajeev Samant, Bakhos Tannous, Krishna Bhat, Richard Cerione, Shuxing Zhang, Ichiro Nakano
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2767706679