Breast cancer, which in advanced stages often leads to bone metastasis, is the most frequent malignant tumor and the second deadliest form of cancer among women in the U.S. Skeletal metastasis is associated with imbalanced bone remodeling and eventual bone fracture that contributes to incapacitating pain and loss of mobility. Bone cancer pain remains a significant health problem due to the limited repertoire of analgesics available to treat this pain without negatively influencing the quality of life and "bone health" of the patient. Bone cancer results in a marked influx of pro- and anti- inflammatory hematological cells into the medullary cavity resulting in activation of nociceptors that express cytokine and chemokine receptors. Thus, blockade of these factors may result in a significant attenuation in bone cancer pain. The sustained release of cytokines by both primary tumor cells and invading leukocytes into the tumor microenvironment shapes the immune response to tumor invasion and ultimately mediates the shift in immune balance to the predominantly immunosuppressive state seen with late stage disease. Activation of cannabinoid receptor 2 (CB2), found on immune cells but not neuronal cells, has been shown to inhibit the release of cytokines from leukocytes; this inhibition plays an important role in CB2 agonist's ability to inhibit pain without producing the CNS side effects commonly associated with CB1. Cannabinoids have also been demonstrated in a number of cancer models to modulate the tumor microenvironment via effects specific to the tumor cells as well as regulation of invading leukocytes. Here, we show that the CB2 specific agonist JWH-015 mediates inflammatory factors in vitro and in vivo in the femoral intramedullary cavity in a murine model of bone cancer while simultaneously attenuating breast cancer induced bone pain and promoting overall health of the bone microenvironment. Further, we demonstrate JWH-015's ability to positively modify the systemic balance of regulatory to effector lymphocytes as well as modulate the suppressive function of regulatory T lymphocytes. We also show that JWH-015 attenuates breast cancer cell proliferation in vitro in a concentration dependent manner. Finally, utilizing a murine in vivo bioluminescence model, we demonstrate that JWH-015 treatment not only attenuates primary tumor growth, but also rate of metastasis. Taken together, these data establish CB2 as an innovative therapeutic target across multiple stages of breast cancer.

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