Breast cancer (BC) is the most common cancer in women worldwide. Approximately 70-80% of BCs express estrogen receptors (ER), which predict the response to endocrine therapy (ET), and are therefore hormone receptor-positive (HR+). Endogenous cannabinoids together with cannabinoid receptor 1 and 2 (CB1, CB2) constitute the basis of the endocannabinoid system. Interactions of cannabinoids with hypothalamic-pituitary-gonadal axis hormones are well documented, and two studies found a positive correlation between peak plasma endogenous cannabinoid anandamide with peak plasma 17β-estradiol, luteinizing hormone and follicle-stimulating hormone levels at ovulation in healthy premenopausal women. Do cannabinoids have an effect on HR+ BC? In this paper we review known and possible interactions between cannabinoids and specific HR+ BC treatments. In preclinical studies, CB1 and CB2 agonists (i.e., anandamide, THC) have been shown to inhibit the proliferation of ER positive BC cell lines. There is less evidence for antitumor cannabinoid action in HR+ BC in animal models and there are no clinical trials exploring the effects of cannabinoids on HR+ BC treatment outcomes. Two studies have shown that tamoxifen and several other selective estrogen receptor modulators (SERM) can act as inverse agonists on CB1 and CB2, an interaction with possible clinical consequences. In addition, cannabinoid action could interact with other commonly used endocrine and targeted therapies used in the treatment of HR+ BC.

The physiological and pathophysiological roles of sex hormones have been well documented and the modulation of their effects is applicable in many current treatments. On the other hand, the physiological role of endocannabinoids is not yet clearly understood and the endocannabinoid system is considered a relatively new therapeutic target. The physiological association between sex hormones and cannabinoids has been investigated in several studies; however, its involvement in the pathophysiology of common human diseases has been studied separately. Herein, we present the first systematic review of molecular pathways that are influenced by both the cannabinoids and sex hormones, including adenylate cyclase and protein kinase A, epidermal growth factor receptor, cyclic adenosine monophosphate response element-binding protein, vascular endothelial growth factor, proto-oncogene serine/threonine-protein kinase, mitogen-activated protein kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, C-Jun N-terminal kinase and extracellular-signal-regulated kinases 1/2. Most of these influence cell proliferative activity. Better insight into this association may prove to be beneficial for the development of novel pharmacological treatment strategies for many common diseases, including breast cancer, endometrial cancer, prostate cancer, osteoporosis and atherosclerosis. The associations between cannabinoids, estrogens and androgens under these conditions are also presented and the molecular interactions are highlighted.

Abstract. The bone remodeling process is influenced by various factors, including estrogens and transmitters of the endocannabinoid system. In osteoblasts, cannabinoid receptors 2 (CB-2) are expressed at a much higher level compared to CB-1 receptors. Previous studies have shown that estrogens could influence CB-2 receptor expression. In the present study, the possible interactions of a specific CB-2 agonist and a specific CB-2 antagonist/inverse agonist with 17-β-estradiol were investigated in primary human osteoblasts (HOB). HOB cells were cultured in phenol red-free osteoblast growth medium (37˚C, 5% CO 2 ). In their 5th passage, HOB were exposed to different concentrations of i) 17-β-estradiol (1, 10 and 100 nM); ii) a specific CB-2 agonist (R,S)-AM1241 (1 and 7.5 µM); and iii) a specific CB-2 antagonist/inverse agonist AM630 (10 µM) and to selected combinations of the substances. After 24 and 48 h of incubation, HOB proliferation activity was measured using a WST-8 assay. Alkaline phosphatase activity was also evaluated using spectrophotometry. Concomitant exposure of HOB to 17-β-estradiol (10 nM) and to specific CB-2 antagonist/inverse agonist (10 µM) showed similar HOB proliferation activity to HOB incubated with 17-β-estradiol only at a 100 nM concentration. By contrast, concomitant incubation of HOB with 17-β-estradiol (10 nM) and specific CB-2 agonist (7.5 µM) resulted in decreased HOB proliferation activity as compared to HOB incubated with 17-β-estradiol only (10 nM). Similar findings were observed after 24 and 48 h of incubation. In all the experiments, HOB successfully passed the alkaline phosphatase differentiation test. In conclusion, for the first time a synergistic interaction between 17-β-estradiol and specific CB-2 antagonist/inverse agonist was observed in HOB. Understanding the molecular pathways of this interaction would be of great importance in developing more efficient and safer drugs for treating or preventing bone diseases.

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