Hydroxytyrosol, a component of olive oil for breast cancer prevention in women at high risk of cancer

Abstract 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 25mg/day oral dose of HT were given for 12 months in pre- and post-menopausal 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 non-significant change; however, in women 60 years or older, the max VBD% decrease was significant (3.7%, p=0.0391), especially in those with high baseline mammographic density. Using RNA-Seq, 3,330 unique transcripts were identified (p<0.05). Mitotic telophase/cytokinesis, DNA damage were upregulated, whereas Wnt, Notch, and Oxidative stress-induced senescence pathways were downregulated (p<0.05). These pathways were confirmed by Nano string n counts where significant decrease in proliferative genes (RELA and CDK4), Wnt pathway (R-HSA-195721 and R-HAS-201681) were observed (p< 0.05). Conclusions Hydroxytyrosol significantly reduced breast density only in women over 60 years, especially in those with high baseline breast density. HT also reduced proliferation and affected 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.