Abstract A64: Identification of p75NTR/TrkB-BDNF axis in breast cancer brain metastasis

Abstract

Abstract Metastasis of breast cancer to the brain is increasing and is a significant cause of morbidity and mortality for breast cancer patients. In order to understand the molecular mechanisms controlling metastasis to the brain, we have generated two mouse models of breast cancer brain metastasis (4T1.luc2.Br5, Eo771.Br5) via serial selection of these cells through the brains of syngeneic mice following carotid artery injection. In vitro, the 4T1.luc2.Br5 cells exhibit increased proliferation and invasion through basement membrane proteins, while both models demonstrate increased ability to adhere to brain microvascular endothelial cells. Transcriptional profiling followed by Western analysis determined that the p75NTR neurotrophin receptor and its ligand BDNF are highly upregulated in brain-metastatic 4T1.luc2.Br5 cells. The TrkB neurotrophin receptor for BDNF is expressed by these cells as well. Knockdown of p75NTR abolishes the increased invasive capacity of brain-selected 4T1.luc2.Br5 in vitro, confirming a role for p75NTR signaling in invasion. While p75NTR expression in primary breast epithelial cells is reportedly low, we observed that 8 of 12 (67%) human breast cancer brain metastasis specimens express high levels of p75NTR, further suggesting an important role in metastasis to brain. Interestingly, while the brain metastatic Eo771.Br5 cells do not express p75NTR in vitro, both the TrkB receptor and its BDNF ligand are upregulated compared to parentals. Together these data suggest a role for activation of p75NTR/TrkB-BDNF signaling in breast cancer brain metastatic cells, and that targeting this pathway may be a means to prevent or treat breast cancer brain metastasis. Citation Format: Wenhong Chen, Christine N. McMahan, Keith D. Barlow, Dennis Juarez, Linda J. Metheny-Barlow. Identification of p75NTR/TrkB-BDNF axis in breast cancer brain metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A64.