| dc.description.abstract | Overexpression of the receptor tyrosine kinase HER2 (ERBB2) leads to an aggressive form of breast cancer. In the past two decades many HER2-targeted therapies have been developed that have increased patient survival, however metastatic patients often develop resistance to these treatments. HER2 expression has been shown to induce the expression of cannabinoid receptor 2 (CB2), which relates to a more aggressive phenotype, increased rates of metastasis, and a worse prognosis. Targeting CB2 in HER2+ breast cancer represents a novel way to decrease protumourigenic signalling and overcome HER2-target treatment resistance. To understand the role of CB2 in promoting tumourigenesis and its potential as a therapeutic target, I engineered a CB2 expression system in HER2+ breast cancer cell lines. Using this system in 2D and 3D models, we demonstrate that CB2 expression increases migration and invasion, which is abrogated with cannabinoid treatment. CB2 expression leads to metabolic rewiring, increased ATP production and increased protection against oxidative stress. The resulting metabolic phenotype reproduces that of cancer stem cells (CSCs), and we observed CB2-dependent increased stemness, shown by mammosphere formation, which was reduced upon cannabinoid treatment. Moreover, CB2 increased Wnt/β-catenin signalling, leading to the expression of the stem cell marker ALDH1A1. We also report that CB2 expression increases PYK2, AKT, and PDL1, driving 3D invasion and immune escape. Taken together, these data suggest that CB2 expression in HER2+ breast cancer induces a migratory CSC-like phenotype that is highly invasive and potentially facilitates immune evasion, thereby promoting metastasis. The expression of CB2 could be an important biomarker for a less favourable prognosis in HER2+ breast cancer. Using CB2-targeting therapies in conjunction with traditional treatments could lead to reduced metastasis, reduced tumour recurrence and improved patient outcomes. | en_US |
