Abstract 23: Chemotherapy and tau interplay facilitates breast-to-brain metastasis

Abstract

Abstract Breast cancer represents the second most common cause of brain metastasis with the rate of 10-16% after lung cancer. The overall survival in brain metastatic patients is very short ranging from 2 to 25 months. Considering the high incidence of brain metastasis and the limitation of available therapies, developing preventive strategies and early detection methods are required to improve the survival rate in the patients. Many primary and brain metastatic breast cancer patients represent cognitive deficits. Besides, chemo-treated breast cancer patients show memory problems before brain metastases diagnosis. Although the cause of cognitive impairments after chemotherapy have not been explored, a recent study revealed that chemotherapy promotes breast cancer metastasis. Correspondingly, our mRNA expression analysis showed downregulation of the tight junction markers in chemo-treated choroid plexus cells (CPs), suggesting that chemotherapy is likely to cause an increase in the blood-cerebral spinal fluid barrier (BCSFB) permeability. Chemotherapy also induces upregulation of tau expression in CP cells. Tau is known as a pathological hallmark of Alzheimer's disease (AD) and neurodegenerative disorders. The abnormally phosphorylated and aggregated form of tau play critical role in neurodegenerative diseases as of AD. Tau expression, both at the mRNA and protein level, is significantly elevated in breast to brain metastases (BBMs). Therefore, we hypothesized that chemotherapy upregulates tau expression in breast cancer cells leading to the BCSFB and blood-brain barrier (BBB) permeability, and consequently, breast to brain metastasis and neurodegeneration. To test our hypothesis, the effect of chemotherapy on the BCSFB and BBB permeability were investigated using the trans endothelial electrical resistance (TEER) and migration assays in the in vitro models. Our results show an increase in abnormal tau expression in chemo-treated primary breast cancer cells. BBM-derived tau is abnormal and forms paired helical filaments (PHFs), similar to Alzheimer's. We conclude that breast to brain metastasis is facilitated through an interplay between chemotherapy, and tau expression and release from breast cancer cells. Additionally, we suggest that tau plays a key role in neurodegeneration defects in brain metastatic patients. This study opens a new path towards prevention and early detection of breast cancer metastasis to the brain, cognitive decline and neurodegeneration in metastatic patients. Citation Format: Behnaz Saatian, Krutika Deshpande, Alex Julian, Brooke Naomi Nakamura, Ling Shao, Josh Neman. Chemotherapy and tau interplay facilitates breast-to-brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 23.