Estrogen receptor modulation by a newly-identified cannabinoid in a preclinical model of breast cancer

Abstract

Background Breast cancer is a diverse group of diseases comprising subtypes with distinct behavior and response to therapy. Tumors that express estrogen receptor alpha (ERα) and depend on estrogen constitute ∼65% of all breast cancer cases. Common endocrine therapy for this kind of breast cancer includes Selective Estrogen Receptor Modulators (SERMs) such as tamoxifen. However, despite the clear benefits, many patients do not complete the recommended 5 and sometimes 10 years of treatment because of adverse effects. Medical cannabis is increasingly used by cancer patients, primarily for palliative care, yet its direct antitumor potential in breast cancer remains poorly understood. Purpose Examine whether cannabis-derived compounds exert selective antitumor effects in breast cancer and elucidate the underlying molecular mechanisms. Study design A combination of in vitro experiments in multiple ER-positive breast cancer cell lines with in vivo validation in an estrogen-dependent xenograft mouse model. Methods Breast cancer cell lines representing different molecular subtypes were evaluated. A panel of chemically distinct cannabis extracts was initially screened for cytotoxic activity and subsequently tested in combination with SERMs. Extracts were chemically profiled using ESI-LC/MS. Phytocannabinoid fractionation, chemical analyses, and structural elucidation were performed to isolate and characterize the bioactive phytocannabinoid in the only cannabis extract identified in the initial screen as effective in combination with tamoxifen. The mechanism of action of this phytocannabinoid was investigated in vitro using molecular and biochemical assays. Finally, antitumor efficacy was assessed in vivo using an estrogen-dependent ER-positive breast cancer xenograft mouse model. Results We found a unique cannabis extract, CANN14, capable of sensitizing ER-positive breast cancer cells to the cytotoxic effect of tamoxifen. We identified a novel phytocannabinoid 373.15b that mimicked the effect of the whole extract without any toxicity by itself. It has a unique structure of a dihydroxyphenol with an acetate group attached to the aromatic ring, distinguishing it from known cannabinoid scaffolds. Cannabinoid 373.15b modulated estrogen signaling by decreasing the mRNA and protein expression levels of ERα, as well as its transcriptional activity, possibly through a signaling pathway involving RASSF1A and Hippo signaling components. In an in vivo mouse model, treatment with 373.15b reduced tumor volume and weight, with a more profound effect when combined with tamoxifen. Conclusion The work presented here identifies a novel cannabinoid that modulates ERα signaling and enhances the antitumor efficacy of SERMs. The findings suggests that co-therapy of 373.15b with SERMs may allow dose reduction of conventional therapy, and by that, diminish the associated adverse effects and improve patient quality of life. One-sentence summary The newly identified cannabinoid 373.15b reduces ERα expression and activity through RASSF1A and Hippo signaling pathway thus exerting antitumor effects.

The authors' abstract, as published at the source. Biomedicine & Pharmacotherapy, 2026 · DOI ↗