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

Cohen V.; Besser E.; Shotan S.; Procaccia S.; Halle-Bikovski A.; Litvinsky S.; Truman M.; Harel M.; Thaler S.; Meiri D. · Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2026

**Background & Methods** This preclinical study evaluated cannabis-derived compounds for antitumor activity in ER-positive breast cancer using in vitro experiments across multiple cell lines combined with in vivo validation in an estrogen-dependent xenograft mouse model. A panel of chemically distinct cannabis extracts was screened for cytotoxic activity, chemically profiled, and tested in combination with tamoxifen (a selective estrogen receptor modulator), with mechanism of action investigations performed using molecular and biochemical assays. **Key Findings** - A novel phytocannabinoid designated 373.15b was identified from cannabis extract CANN14, featuring a unique dihydroxyphenol structure with an acetate group attached to the aromatic ring that distinguishes it from known cannabinoid scaffolds. - Cannabinoid 373.15b sensitized ER-positive breast cancer cells to tamoxifen by decreasing ER-alpha mRNA and protein expression levels and suppressing its transcriptional activity, potentially through RASSF1A and Hippo signaling pathway modulation. - In vivo mouse model studies demonstrated that 373.15b monotherapy reduced tumor volume and weight, with significantly more profound effects when combined with tamoxifen. **Dosage & Administration** Not reported. The study was conducted in preclinical models without human dosing information or administration route specifications for therapeutic translation. **Safety & Adverse Effects** The novel phytocannabinoid 373.15b demonstrated no inherent toxicity when administered as monotherapy. The authors propose that combination therapy with 373.15b and SERMs may enable dose reduction of conventional endocrine therapy, potentially diminishing associated adverse effects and improving patient quality of life. However, comprehensive safety and toxicity profiling in animal models and human studies has not been reported. **Evidence Quality** This is a preclinical review-based study with significant limitations. Evidence is derived from in vitro cell line experiments and a single xenograft mouse model, representing early-stage translational research. No human clinical trials have been conducted. The study lacks information on optimal dosing, bioavailability, pharmacokinetics, and long-term safety profiles. The novel cannabinoid 373.15b requires substantial additional characterization before human evaluation. Results are promising but represent proof-of-concept findings requiring validation through IND-enabling studies and subsequent clinical trials before therapeutic application.

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