Estrogen Receptor Modulation by a Newly-Identified Phytocannabinoid in a Preclinical Model of Breast Cancer
Breast cancer is made up of different subtypes that respond differently to treatments. Tumors that express estrogen receptor alpha (ERα) and depend on estrogen for propagation constitute 60%-70% of all cases. They are commonly treated with endocrine therapy such as Selective Estrogen Receptor Modulators (SERMs), the best known of which is Tamoxifen. However, despite its obvious benefits, many patients that start Tamoxifen therapy do not complete the whole time-course because of adverse effects. Here, we identified a novel phytocannabinoid from whole extracts of Cannabis, which we termed 373.15b, that was able to prime ER-positive tumors to the cytotoxic effect of tamoxifen without any toxicity by itself. Thus, allowing the use of significantly lower doses while still achieving the same outcome. A similar effect of 373.15b was demonstrated in combination with other types of SERMs as well. 373.15b affects estrogen signaling by decreasing the protein expression levels of ERα and its transcriptional activity. We show its mechanism of action involves the modulation of the Hippo signaling pathway. Our work suggests that co-therapy for ER-positive breast cancer patients with SERMs and 373.15b can reduce the treatment dosage of the conventional therapy and by that diminish the associated adverse effects and improve patient quality of life.