title: Delta9-tetrahydrocannabinol inhibits cell cycle progression in human breast cancer cells through Cdc2 regulation.
abstract: It has been proposed that cannabinoids are involved in the control of cell fate. Thus, these compounds can modulate proliferation, differentiation, and survival in different manners depending on the cell type and its physiopathologic context. However, little is known about the effect of cannabinoids on the cell cycle, the main process controlling cell fate. Here, we show that Delta(9)-tetrahydrocannabinol (THC), through activation of CB(2) cannabinoid receptors, reduces human breast cancer cell proliferation by blocking the progression of the cell cycle and by inducing apoptosis. In particular, THC arrests cells in G(2)-M via down-regulation of Cdc2, as suggested by the decreased sensitivity to THC acquired by Cdc2-overexpressing cells. Of interest, the proliferation pattern of normal human mammary epithelial cells was much less affected by THC. We also analyzed by real-time quantitative PCR the expression of CB(1) and CB(2) cannabinoid receptors in a series of human breast tumor and nontumor samples. We found a correlation between CB(2) expression and histologic grade of the tumors. There was also an association between CB(2) expression and other markers of prognostic and predictive value, such as estrogen receptor, progesterone receptor, and ERBB2/HER-2 oncogene. Importantly, no significant CB(2) expression was detected in nontumor breast tissue. Taken together, these data might set the bases for a cannabinoid therapy for the management of breast cancer.
authors.affiliation: Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain.
authors.forename: María M
authors.initials: MM
authors.lastname: Caffarel
authors.forename: David
authors.initials: D
authors.lastname: Sarrió
authors.forename: José
authors.initials: J
authors.lastname: Palacios
authors.forename: Manuel
authors.initials: M
authors.lastname: Guzmán
authors.forename: Cristina
authors.initials: C
authors.lastname: Sánchez
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D016203:CDC2 Protein Kinase / Q000096:biosynthesis* / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D013759:Dronabinol / Q000494:pharmacology*; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D043884:Receptor, Cannabinoid, CB1 / Q000096:biosynthesis / Q000235:genetics; D043885:Receptor, Cannabinoid, CB2 / Q000096:biosynthesis / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D013759:Dronabinol; D016203:CDC2 Protein Kinase