Estrogen Receptor Modulation by a Newly-Identified Phytocannabinoid in a Preclinical Model of Breast Cancer

Breast cancer is a diverse group of diseases made of subtypes with distinct behavior and response to therapy. Tumors that express estrogen receptor alpha (ERα) and depend on estrogen for cell proliferation constitute 60%-70% of all cases. Common endocrine therapy for this kind of breast cancer is Selective Estrogen Receptor Modulators (SERMs) such as tamoxifen. However, despite the obvious benefits of tamoxifen, many patients that start tamoxifen therapy do not complete the whole time-course because of adverse effects. A new and promising emerging field in cancer treatment is medical Cannabis. Here, we identified a novel phytocannabinoid, termed 373.15b, that was able to sensitize ER-positive tumors to the cytotoxic effect of tamoxifen without any toxicity by itself. 373.15b affected estrogen signaling by decreasing the protein and RNA expression levels of ERα and reducing its transcriptional activity via a signaling pathway involving RASSF1A, AKT1 and YAP. A similar effect of 373.15b was demonstrated in combination with other SERMs such as Toremifene citrate and 4-Hydroxytamoxyfen. In an in-vivo mice model, treatment with 373.15b by itself reduced tumor volumes and weights, but the effect was more profound when combined with tamoxifen. Our work suggests that co-therapy with 373.15b might reduce the treatment dosage of conventional therapy and by that diminish the associated adverse effects and improve patient quality of life.