Hydroxytyrosol, a Component of Olive Oil for Breast Cancer Prevention in Women at High Risk of Cancer

Background: This study evaluates the effects of hydroxytyrosol (HT), a component of olive oil, on mammographic breast density reduction. We explored effects of HT on Wnt β-catenin and other pathways involved in cancer stem cell renewal, DNA repair, cell proliferation, and differentiation. Methods: Twenty-five milligrams per day oral dose of HT was given for 12 months in pre- and postmenopausal women at increased risk of breast cancer. Out of 51 patients enrolled, 41 completed the study. The annualized percent decrease in maximum mammographic volumetric breast density (max VBD%) between baseline (BL) and end of treatment (EOT) was analyzed. RNA sequencing (RNA-Seq) and multiplex analysis was performed on the breast biopsies to compare the BL with EOT samples. Results: Max VBD% showed a nonsignificant change; however, in women 60 years or older, the max VBD% decrease was significant (3.7%, p = 0.0391), especially in those with high BL mammographic density. Using RNA-Seq, 3330 unique transcripts were identified (p < 0.05). Mitotic telophase/cytokinesis and DNA damage were upregulated, whereas Wnt, Notch, and oxidative stress-induced senescence pathways were downregulated (p < 0.05). These pathways were confirmed by NanoString nCounter where significant decrease in proliferative genes (RELA and CDK4) and Wnt pathway (R-HSA-195721 and R-HAS-201681) was observed (p < 0.05). Conclusions: HT reduced breast density only in women over 60 years, especially in those with high BL breast density. HT also reduced proliferation and affected the Wnt signaling pathway. This study lays the foundation for future larger studies in exploring a natural compound with well tolerability and overall nontoxic profile for chemoprevention of breast cancer. Trial Registration: ClinicalTrials.gov identifier: NCT02068092.