PAQR5 Membrane Progesterone Receptor Regulates the Blood–Brain Barrier during Brain Metastasis Formation

Abstract Brain metastases are a common and often fatal complication of certain cancer types, such as triple-negative breast cancer. However, the molecular pathways driving brain metastasis formation, including the migration of cancer cells from the bloodstream to the brain parenchyma across the blood–brain barrier, are not yet fully defined. Therefore, using highly relevant mouse and human model systems, the mechanisms by which triple-negative breast cancer cells and their released extracellular vesicles modulate the blood–brain barrier-forming endothelium to increase its permissiveness to tumour cell entry into the brain are investigated. It is observed that extracellular vesicles derived from tumour cells are taken up by cerebral endothelial cells, where they induce miR-146a-5p- and TGF-β1-mediated downregulation of PAQR5/mPRγ, a membrane progesterone receptor. This, in turn, leads to disruption of interendothelial tight junctions, particularly through repression of claudin-5 expression, a critical protein for maintaining barrier function. Altogether this identifies a novel mechanism by which triple-negative breast cancer-derived extracellular vesicles compromise blood–brain barrier integrity, thereby facilitating transendothelial migration of cancer cells and promoting brain metastasis development. Moreover, this study is the first to highlight the role of membrane progesterone receptors in regulating the blood–brain barrier. Table of contents Extracellular vesicles from triple-negative breast cancer cells induce miR-146a-5p- and TGF-β1-mediated downregulation of PAQR5/mPRγ, a membrane progesterone receptor, in blood–brain barrier-forming endothelial cells. This results in disruption of interendothelial tight junctions, thereby promoting enhanced migration of cancer cells into the brain. This mechanism highlights the role of membrane progesterone receptors in regulating the blood–brain barrier.