Cannabinoids reduce ErbB2-driven breast cancer progression through Akt inhibition

Our results show that both Δ9-tetrahydrocannabinol, the most abundant and potent cannabinoid in marijuana, and JWH-133, a non-psychotropic CB2 receptor-selective agonist, reduce tumor growth, tumor number, and the amount/severity of lung metastases in MMTV-neu mice. Histological analyses of the tumors revealed that cannabinoids inhibit cancer cell proliferation, induce cancer cell apoptosis, and impair tumor angiogenesis. Cannabinoid antitumoral action relies, at least partially, on the inhibition of the pro-tumorigenic Akt pathway. We also found that 91% of ErbB2-positive tumors express the non-psychotropic cannabinoid receptor CB2.Taken together, these results provide a strong preclinical evidence for the use of cannabinoid-based therapies for the management of ErbB2-positive breast cancer.Breast cancer represents approximately 30% of newly diagnosed cancers each year. Almost one third of them overexpresses the ErbB2 tyrosine kinase receptor (Her2 in humans, Neu in rats), a member of the EGF receptor family [1]. Phosphorylation of their intracellular domains upon engagement by their ligands induce receptor homo- or heterodimerization, leading to the activation of key signaling pathways that promote cell proliferation and survival, including the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and the ERK/MAPK cascade. Although no specific ligand for ErbB2 has been identified yet, this receptor is the preferred heterodimerization partner of the family [2]. ErbB2-overexpressing breast tumors are characterized by very aggressive clinical courses and decreased survival rates, mostly due to the poorly differentiated, highly proliferative and highly invasive nature of their constituent cells [2]. All these characteristics make ErbB2-overexpressing tumors less responsive to conventional therapies. One of the most recent advances in the treatment of these tumors is the use of a humanized neutralizing monoclonal antibody against ErbB2 (Trastuzumab) [3]. Although this strat