The Endocannabinoid System as a Target for Treatment of Breast Cancer

During the present funding cycle, we have focused on in vitro approaches to determine the influence of the endogenous cannabinoid system on breast cancer. Studies of transformation in cell culture have demonstrated that the combination of estrogen and benzopyrene alters the phenotype of MCF-10a cells, a normal breast epithelial cell line, to that of a tumor cell. This conclusion is based on induction of anchorage independent growth, loss of acini structure formation in 3D cultures, and the ability to proliferate in the absence of exogenous growth factors normally required for MCF-10a growth. We are now prepared to examine the influence of cannabinoid agonists and antagonists on the transformation process. We further initiated studies to evaluate the interactions of cannabinoids with conventional chemotherapy in breast tumor cell lines. Our studies are consistent with a mixture of additive and synergistic effects in the three cell lines MCF-7, MDA-MB-231, and 4T1 and three cannabinoid combinations THC, CBD, and Win55 in combination with Adriamycin. Our studies also strongly suggest that the interactions are most pronounced in breast tumor cells lacking functional p53. Studies are now in progress to evaluate the cannabinoids in combination with other drugs utilized in the treatment of breast cancer including paclitaxel, methotrexate and 5-fluorouracil. In addition, we have established the in vivo model of 4T1-luc cells that can be monitored in real time in an immunocompetent mouse and plan to extend the cell culture work of cannabinoids chemotherapy to this experimental system.