The Role of HER2-CB2 Heteromers in The Progression of Breast Cancer

The Role of HER2-CB2 Heteromers in The Progression of Breast Cancer
Cannabinoids derived from the plant Cannabis sativa (phytocannabinoids), e.g. Delta 9-tetrahydrocannabinol (THC), have been used to treat a variety of ailments over millennia. Recently, the receptors for these phytocannabinoids have been identified, cannabinoid receptor 1 and 2 (CB1R and CB2R), along with their endogenous ligands 2-Arachidonoylglycerol (2-AG) and anandamide (AEA). The majority of CB2R expression in healthy tissues is principally restricted to the cells immune system, however CB2R is also implicated in numerous human diseases, and particularly cancer. CB2R expression is closely associated with the expression of Human Epidermal Growth Factor Receptor 2 (HER2) in breast cancer and is thought to potentiate progression to invasive breast cancer. HER2 activation has been reported to directly increased CB2R expression in an ELK-dependent mechanism. Once expressed CB2R travels to the plasma membrane and forms functional heteromers with HER2. Signalling through HER2-CB2R heteromers potentiate cancer cell growth, increasing proliferation and angiogenesis and suppress apoptosis. Furthermore, the administration of THC leads to the senescence of cancer cell growth and an increase in apoptosis. THC was found to cause the dissociation of the HER2-CB2R heteromer and leads to proteasomal degradation of HER2.
To further investigate the functional role of HER2-CB2R heteromer in the progression of breast cancer I will utilise 3D models of ductal carcinoma in situ (DCIS) to measure the invasive phenotype of HER2 and CB2R expressing cells. Ductal carcinoma in situ (DCIS) is the non-invasive growth of luminal cells in the breast duct. Whilst DCIS can be asymptomatic and has low morbidity, it can progress to invasive breast cancer, where the luminal cells invade out of the duct and metastasise to other sites in the body. Previous work in the lab developed a 3D model DCIS using the MCF10A breast luminal cell line, with the DCIS phenotype induced with the HER2 expression. I am to replicate this model with MCF10A that contain cumate inducible CB2R to analyse the formation of HER2-CB2R dimers and interpret the effect of CB-2R expression and concurrent HER2 and CB2R expression on DCIS progression and invasion. I will identify signalling pathways that activate after HER2 and CB2R expression and elucidate their role in DCIS progression and elucidate the effect of cannabinoid ligands on this process.
After the role of HER2 and CB2R in DCIS progression is established we will then investigate other factors influencing DCIS progression, such as the role of the immune system. CB2R is expressed on B cells, monocytes, macrophages and T cells; agonists of CB2R may therefore influence the anti-tumour immunity in the tumour microenvironment. In fact, THC may decrease anti-tumour immunity by suppressing CB2R expressing immune cells. Therefore, the addition of either primary immune cells or cell lines to the 3D DCIS model will help elucidate how CB2-R-expressing immune cells influence DCIS progression.
Finally, we can investigate the role of CB2R in other cancers similar to breast cancer such as prostate and other epithelial cancers that have been reported to have HER2 and CB2R expression. Although the expression rates of HER2 vary, the majority of cancers express at least one of the HER family receptors (EGFR, HER2, HER3, HER4), and therefore CB2R may interact with them to regulate cancer signalling. Investigation of CB2R forming dimers with other HER-family members may increase the potential of CB2R-targetted therapies in treating several types of cancer. This highlights the importance of CB2R signally in the progression of variety of cancers, and the potential therapeutic benefit of targeting HER2-CB2R signalling.