Brain metastasis (BrM) occurs in 10–15% of patients with estrogen receptor–positive breast cancer (ER + BC) and remains a major clinical challenge with limited therapeutic options. Median survival after BrM diagnosis is approximately 18 months, underscoring the need for new druggable targets. We previously identified recurrent overexpression of the receptor tyrosine kinase RET in BrM relative to matched primary tumors. RET’s principal ligand, Glial Cell-Derived Neurotrophic Factor (GDNF), is highly expressed in the brain. Here, we show that RET expression and GDNF-responsive gene signatures are elevated in BrM from ER + BC patients. RET signaling promotes metastatic phenotypes in vitro, all of which are suppressed by Pralsetinib, a potent RET-selective inhibitor. Using RET-overexpressing and RET-deficient ER + BC models, we demonstrate that RET activation enhances downstream signaling and drives metastatic behaviors in vitro, ex vivo, and in vivo. In ex vivo mouse brain slice co-culture, RET overexpression increases colonization and invasion, which are abrogated by Pralsetinib or RET knockdown. In vivo, RET overexpression enhances brain colonization and reduces survival. Proteomic profiling reveals novel GDNF-mediated signaling interactions, including PLCγ, P70S6K, STAT3, and CREB. These findings identify RET as a targetable driver of BrM from ER + BC and support therapeutic targeting of RET in affected patients.
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