Sakuranetin modulates estrogen receptor signaling in breast cancer cells

Identification of natural, bioactive compounds has been of interest to the biomedical field, in particular for the treatment of cancer. Flavonoids are a family of compounds, present across many plant species, known for their polyphenolic structure that results in cellular bioactivity. The flavonoid, sakuranetin, is produced due to external stressors, through the naringenin biosynthetic pathway. Binding affinity and docking simulations confirmed sakuranetin binding to the estrogen receptor alpha (ERα) pocket in a manner similar to, but with weaker affinity than 17β-estradiol (E2). Due to sakuranetin having chemical similarities to estrogen, this study evaluated the potential of sakuranetin to act as an endocrine modulator in estrogen receptor-positive (ERα+) breast cancer cell lines. In the ERα + cell lines, MCF-7 and T-47D, sakuranetin treatment induced dose-dependent estrogenic activity (≥ 10 μM). Sakuranetin significantly increased colony formation and cell proliferation in the MCF-7 cell line. Breast cancer cell lines with constitutively active ER through an inserted mutation in the ERα (Y537S) demonstrated no significant changes in estrogenic activity or cellular proliferation following sakuranetin treatment, except at an elevated dose (50 μM). Finaly, sakuranetin treatment enhanced genes associated with ER signaling and significantly increased ERα-mediated gene (PGR and CXCL12) expression. These results support the role of sakuranetin as a natural estrogenic compound.