Treatment options for brain metastatic
breast cancer are limited because the molecular mechanism for how
breast cancer cells infiltrate the brain is not fully understood. For
breast tumors to metastasize to the brain first, cells need to detach from the primary
tumor, enter in the blood circulation, survive within the microvascular niche, and then cross the blood-brain barrier (BBB) to colonize into the brain. It is critical to understand how
breast cancer cells transmigrate through the BBB to prevent brain
metastasis.
Nuclear respiratory factor 1 (
NRF1) transcription factor has been reported to be highly active in several human
cancers and its aberrant expression facilitates in the acquisition of
breast cancer stem cells (BCSCs).
Inhibitor of differentiation protein 3 (ID3), a transcription regulating
protein, induces pluripotent endothelial stem cells (ESCs). Herein, we investigated if NRF1-induced BCSCs could cross a BBB model and guiding of BCSCs by ID3-induced ESCs across the BBB. BCSCs and ESCs were subjected to functional gain/loss experiments to determine if NRF1/ID3 contributed to lineage-specific BCSCs organ entry. First, we tested whether NRF1 promoted migration of
breast cancer using a BBB model consisting of BCSCs or MDA-MB231 cells, brain endothelial cell layer, and astrocytes. NRF1 overexpression increased the propensity for BCSCs and NRF1-induced MDA-MB231 cells to adhere to brain endothelial cells and migrate across a human BBB model. Increased adhesion of NRF1-induced BCSCs to ESCsID3 was detected. NRF1-induced BCSCs crossed through the BBB model and this was promoted by ESCsID3. We also showed that environmental relevant exposure to
PCBs (
PCB153 and PCB77) produced differential effects. Treatment with
PCB153 showed increased growth of NRF1-induced BCSCs
tumor spheroids and increased in vivo migration of ESCsID3. Exosomal ID3 released from endothelial cells also supported the growth of NRF1-induced BCSCs and provide the basis for paracrine effects by ESCsID3 associated with
breast tumors. Xenograft experiments showed that ID3 overexpressing brain ESCs not only supported the growth of BCSC
tumor spheroids but guided them to the neural crest in zebrafish. These findings show for the first time a novel role for ID3 and NRF1 by which ESCsID3 help guide BCSCsNRF1 to distant metastatic sites where they most likely facilitate the colonization, survival, and proliferation of BCSCs. This knowledge is important for pre-clinical testing of NRF1/ID3 modifying agents to prevent the spread of
breast cancer to the brain.