Resveratrol analogues surprisingly effective against triple‑negative breast cancer, independent of ERα

Resveratrol, a plant‑derived stilbene compound, has exhibited anticancerous properties, including breast cancer. Stilbenes have a molecular structure highly similar to estrogen and have the ability to bind estrogen receptors and regulate activity. Numerous studies have demonstrated the effectiveness of resveratrol in estrogen receptor‑positive (ER‑positive) subtypes of breast cancer, yet the effects in ER‑negative subtypes, including triple‑negative breast cancer (TNBC), have been limited. In the present study, resveratrol and 28 analogues were tested on a panel of ER‑positive and TNBC cell lines to determine effects on cell viability. Several compounds exhibited significant impacts on cell viability and suggested changes in cell morphology, with high potency of select compounds compared to resveratrol observed in a dose‑dependent manner. Due to the lack of estrogen receptors in TNBC and the estrogenic nature of stilbenes, regulation of breast cancer‑associated cellular pathways was assessed for five analogues shown to significantly inhibit cell viability. Top regulated pathways included apoptosis (confirmed by caspase assay) and DNA damage repair. Overall, our results indicated several resveratrol analogues to be active in ER‑negative phenotypes, acting through an ER receptor‑independent manner, supporting further investigation into their mechanism of action and use as potential chemotherapeutics in higher‑risk breast cancer cases.