Role of breast cancer secreted miRNA in brain metastasis

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PROJECT SUMMARY/ABSTRACT Breast cancer metastasis to the brain is rising in prevalence and is an increasingly lethal threat to patients due to the very limited treatment options and high mortality. Therefore, there is a great and urgent need to develop novel preventive and therapeutic treatments for brain-homing metastatic cancer. Altered function of normal cells in a metastatic niche has been recognized as an important means for cancer to facilitate metastasis. The metabolic reprogramming of normal niche cells during cancer metastasis, however, remains largely unexplored. The proposed project will investigate this unique aspect of cancer–host crosstalk from the novel perspective of extracellular miRNA, whose function in transferring cancer-derived signals to various types of niche cells to facilitate cancer growth and metastasis has been recently recognized. MiRNA negatively regulates gene expression through inducing mRNA degradation and/or translation blockade. The goals of this study are to identify the mechanism by which cancer cell-secreted miRNA reprograms the energy metabolism of brain cells (neurons and astrocytes) to promote metastasis, to assess potential therapeutic strategies to protect the brain using experimental models, and to evaluate the potential of such miRNA as a novel blood-based biomarker for breast cancer brain metastasis. In Aim 1, we will determine the effects and acting mechanism of selected breast cancer-secreted miRNA in the metabolic reprogramming of brain cells and tissues, including a mechanism through suppression of nutrient influxes. Mouse models will be used to elucidate how altered energy metabolism in the brain contributes to the stepwise process of breast-to-brain metastasis. In Aim 2, we will assess the beneficial effects of experimental therapeutics targeting cancer-induced adaptation of the brain as novel strategies to prevent or treat breast cancer brain metastasis. In Aim 3, we will evaluate the potential of circulating miRNA as a clinical biomarker for the prediction or early diagnosis of brain metastasis in breast cancer patients. We will also investigate specimens of resected brain metastases for clinical evidence of the herein identified molecular mechanism. The proposed project will provide a novel perspective to our understandings of the dynamic communication between cancer and host and of the complex mechanisms underlying the development of brain metastases. It may establish rationales for novel therapeutic strategies to prevent or treat brain-metastasizing cancer and alleviate cancer’s adverse effects on brain function, which is our long-term objective. Importantly, our study may establish circulating miRNA as a non-invasive biomarker to identify patients with a high risk of developing brain metastases, thereby enabling a shift of our therapeutic focus to targeting the prevention of brain metastases.