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⁹-Tetrahydrocannabinol Inhibits Cell Cycle Progression in Human Breast Cancer Cells through Cdc2 Regulation

¹ Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University and ² Breast and Gynecological Cancer Group, Molecular Pathology Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

Requests for reprints: Cristina Sánchez, Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain. Phone: 34-913944668; Fax: 34-913944672; E-mail: csg{at}bbm1.ucm.es.

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 ⁹-tetrahydrocannabinol (THC), through activation of CB₂ 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 G₂-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 CB₁ and CB₂ cannabinoid receptors in a series of human breast tumor and nontumor samples. We found a correlation between CB₂ expression and histologic grade of the tumors. There was also an association between CB₂ expression and other markers of prognostic and predictive value, such as estrogen receptor, progesterone receptor, and ERBB2/HER-2 oncogene. Importantly, no significant CB₂ 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.(Cancer Res 2006; 66(13): 6615-21)

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