Brain metastasis poses a challenge in cancer treatment due to its prevalence, diagnostic complexities, and the limited efficacy of systemic therapies due to the blood brain barrier (BBB). Previous work in our lab utilized patient-derived Circulating Tumor Cell (CTC) lines established from the peripheral blood of patients with metastatic luminal breast cancers to investigate the molecular features that allow a subset of CTCs to adapt and grow in the brain. This study identified Semaphorin 4D (SEMA4D), a transmembrane receptor that facilitates BBB transmigration, both in vitro and in vivo, through its interaction with the Plexin B1 (PLXNB1) receptor. Together with oncogene MYC, SEMA4D facilitates the colonization of the brain and promotes brain metastasis of CTCs. In this study, we propose investigating the hypothesis that the reverse signaling via the cytoplasmic region of SEMA4D activates the Yes Associated Protein (YAP) pathway, facilitating BBB transmigration. Our data shows that truncating the cytoplasmic region of SEMA4D (deleting the PDZ binding domain) in the BT474 HER2 positive cell line reduces BBB transmigration. In addition, cells that are overexpressed with SEMA4D showed nuclear localization of YAP via immunofluorescence. Hence, using patient-derived CTC cultures and a model system of breast cancer cell lines we aim to elucidate SEMA4D’s link to YAP signaling and the mechanism of BBB transmigration. Understanding the mechanisms underlying metastatic invasion through the BBB is crucial for developing targeted interventions in the future.