Impact of minor cannabinoids on key pharmacological targets of estrogen receptor-positive breast cancer.

Abstract

Endocrine therapy for estrogen receptor-positive (ER⁺) breast cancer has significantly improved over the last decades. However, it presents some limitations that make the search for novel therapeutic options mandatory. Several studies have been conducted to understand the anti-tumor potential of cannabinoids in breast cancer. Yet, most of them are focused on the major phytocannabinoids Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). However, Cannabis has other minor phytocannabinoids whose anti-cancer properties are still to be elucidated. Here, we investigated the mechanisms of action of four minor cannabinoids, cannabigerol (CBG), cannabidivarin (CBDV), cannabinol (CBN), and cannabichromene (CBC), in 2D and 3D ER⁺ breast cancer models. These cannabinoids dysregulate MCF-7aro cell cycle progression, induce apoptosis by different mechanisms, and inhibit the growth of MCF-7aro spheroids. CBG exerts its effects through a down-regulation of both ER and AR protein levels, while CBDV reduces aromatase protein levels. CBN and CBC simultaneously affect the three targets, ER, aromatase, and AR. In fact, CBN and CBC present an AR-dependent cell death, down-regulate aromatase levels, and act as ER negative regulators impairing cancer cell growth. CBN caused the most pronounced effects. Overall, this study highlights the anti-cancer properties and the therapeutic potential of these minor cannabinoids in ER⁺ breast cancer.