Her2 and TrkB as Dual Therapy Targets for Her2+ Breast Cancer Brain Metastases
Posted May 18, 2018
Rahul Jandial, M.D., Ph.D., City of Hope
Breast cancer frequently metastasizes or spreads, to the bones, lungs, brain, and liver. Over one-third of patients diagnosed with human epidermal growth factor receptor-2 positive (Her2+) primary breast tumors will develop metastases in the brain, even when systemic disease at other sites is in remission. The unique microenvironment in the brain contains neurotrophins and growth factors that regulate the growth, survival, and proper functioning of neurons. Research is needed to identify molecular targets and mechanisms within the brain microenvironment that provide a survival advantage to cancer cells that cross the blood-brain barrier.
Brain-derived neurotrophic factor (BDNF) is a neurotrophin in the brain microenvironment that can bind to the tropomyosin-related kinase B (TrkB) receptor and activate several pathways within cells. With support from a fiscal year 2014 Breast Cancer Research Program Breakthrough Award – Funding Level 1, Dr. Rahul Jandial and his research team sought to elucidate the role of BDNF and TrkB signaling in Her2+ breast cancer brain metastases. In a recent paper published in Breast Cancer Research, Dr. Jandial and his team showed that astrocyte-derived BDNF in the brain microenvironment facilitates the initiation and growth of Her2+ breast cancer metastases in the brain. Human tissue isolated from both the primary tumor and brain metastases from patients with Her2+ or triple negative breast cancer revealed that activated Her2 and TrkB were higher in the tissue isolated from the Her2+ brain metastases compared to the primary tumor and to triple negative breast cancer brain metastases. In addition, Her2 and TrkB were found to be co-localized on the Her2+ breast cancer brain metastases. Dr. Jandial and his team also showed that when patient-derived Her2+ breast cancer brain metastatic cells were injected into mice, colonization in the brain occurred; however, blocking TrkB expression in these cells prevented the formation of significant brain metastases. In addition, the research team showed that BDNF promotes the physical interaction of Her2 and TrkB receptors in patient-derived breast cancer brain metastatic cells.
Data from Dr. Jandial and his team indicate that TrkB could be a potential therapeutic target for the treatment or prevention of brain metastases in patients with Her2+ breast cancer disease. Moreover, treatment with both Her2 and TrkB inhibitors decreased the viability of the metastatic breast cancer cells, supporting the use of dual-targeted therapies for the treatment of Her2+ metastatic breast cancer.
Predicted model of signaling between breast cancer cells and the brain microenvironment. Astrocyte produced BDNF (red) binds the TrkB receptor (purple) on the cell surface of breast cancer cells (green) leading to phosphorylation of the Her2 (orange) and TrkB receptors.
C 2016 Crown copyright
Choy C, Ansari K, Neman J, et al. 2017. Cooperation of neurotrophin receptor TrkB and Her2 in breast cancer cells facilitates brain metastases. Breast Cancer Research 19(1):51.
Last updated Friday, May 18, 2018