Unveiling the mechanism of action behind the anti-cancer properties of cannabinoids in ER + breast cancer cells: impact on aromatase and steroid receptors

Breast cancer is the leading cause of cancer-related death in women worldwide. In the last years, cannabinoids have gained attention in the clinical setting and clinical trials with cannabinoid-based preparations are underway. However, contradictory anti-tumour properties have also been reported. Thus, the elucidation of the molecular mechanisms behind their anti-tumour efficacy is crucial to better understand its therapeutic potential. Considering this, our work aims to clarify the molecular mechanisms underlying the anti-cancer properties of the endocannabinoid anandamide (AEA) and of the phytocannabinoids, cannabidiol (CBD) and Δ⁹-tetrahydrocannabinol (THC), in estrogen receptor-positive (ER⁺) breast cancer cells that overexpress aromatase (MCF-7aro). Their in vitro effects on cell proliferation, cell death and activity/expression of aromatase, ERα, ERβ and AR were investigated. Our results demonstrated that cannabinoids disrupted MCF-7aro cell cycle progression. Unlike AEA and THC that induced apoptosis, CBD triggered autophagy to promote apoptotic cell death. Interestingly, all cannabinoids reduced aromatase and ERα expression levels in cells. On the other hand, AEA and CBD not only exhibited high anti-aromatase activity but also induced up-regulation of ERβ. Therefore, all cannabinoids, albeit by different actions, target aromatase and ERs, impairing, in that way, the growth of ER⁺ breast cancer cells, which is dependent on estrogen signalling. As aromatase and ERs are key targets for ER⁺ breast cancer treatment, cannabinoids can be considered as potential and attractive therapeutic compounds for this type of cancer, being CBD the most promising one. Thus, from an in vitro perspective, this work may contribute to the growing mass of evidence of cannabinoids and cannabinoids-based medicines as potential anti-cancer drugs.