Role of the CB2 Cannabinoid Receptor in ERBB2-Driven Breast Cancer Progression

Eduardo Pérez-Gómez1, Clara Andradas1, María Muñóz Caffarel1,2, Gema Moreno Bueno3, Juana María Flores4, Sandra Blasco-Benito1, Manuel Guzmán1, Cristina Sánchez1. 1Dept. Biochemistry and Molecular Biology I, School of Biology, Complutense Universit, Madrid, Spain, 2Department of Pathology, University of Cambridge, Cambridge, UK, 3Dept. Biochemistry, Autonoma University, Madrid, Spain, 4Dept. Animal Surgery and Medicine, School of Veterinary, Complutense University, Madrid, Spain

A large body of evidence has demonstrated that plant-derived, endogenously produced and synthetic cannabinoids exert antitumoral actions in different models of cancer, including cell cultures, xenografted animals and genetically engineered mice (Velasco et al., Nature Reviews Cancer 2012). They inhibit cancer cell proliferation, adhesion, migration and induce cell death by apoptosis. However, little is known about the role of the endocannabinoid system in tumor physio-pathology. In particular, although strong evidence point to the CB2 cannabinoid receptor as target for anti-cancer therapy, there is no information about its role in tumor generation and progression.

To shed light on this issue, we generated animals with two genetic modifications, specifically, ErbB2 overexpression directed to the mammary epithelium, which triggers the spontaneous generation of breast tumors (Guy et al., PNAS USA 1992), and genetic ablation of the CB2 cannabinoid receptor (Buckley et al., Eur J Pharmacol 2000). Comparing a population of 63 wild type animals with a population of 56 CB2 knockout littermates, we observed that the absence of CB2 receptors produced a striking delay in tumor appearance (p=0.026), reduced the number of tumors generated per animal (p=0.04), slowed down their growth (p=0.008) and diminished the percentage of animals with lung metastasis (p=0.04). We have also observed that animals lacking CB2 receptors present different levels of the endogenously produced cannabinoid anandamide than the corresponding wild type animals (n=8, p=0.038). Preliminary results suggest that the differences in anandamide levels between genotypes may control the general homeostasis of the mammary gland, including its oncogenic transformation and tumor progression.

Finally, we analyzed CB2 receptor protein (n=166) and mRNA levels [in two public microarray databases (Chin et al., Cancer Cell 2006 and Bild et al., Nature 2006)] in human breast cancer samples. We found a direct correlation (p=0.03) between receptor expression and poor prognosis.

Together, these results suggest that CB2 receptors play a pivotal role in ErbB2-driven breast tumor generation and progression.

References:

Bild AH et al, Nature 439:353, 2006

Buckley NE et al, Eur J Pharmacol, 396:141, 2000

Chin K et al, Cancer Cell 10:529, 2006

Guy CT et al, PNAS USA 89:10578, 1992

Velasco G et al, Nature Reviews Cancer 12:436, 2012