HumanBreastTissueDispositionandBioactivityofLimonene in Women with Early-Stage Breast Cancer

Limonene is a bioactive food component found in citrus peel oil that has shown chemopreventive and chemotherapeutic activities in preclinical studies. We conducted an open-label pilot clinical study to determine the human breast tissue disposition of limonene and its associated bioactivity. We recruited 43 womenwithnewlydiagnosedoperablebreastcancerelectingtoundergosurgicalexcisiontotake2gramsof limonenedailyfortwotosixweeksbeforesurgery.Bloodandbreasttissuewerecollectedtodeterminedrug/ metabolite concentrations and limonene-induced changes in systemic and tissue biomarkers of breast cancerriskorcarcinogenesis.Limonenewasfoundtopreferentiallyconcentrateinthebreasttissue,reaching hightissueconcentration(mean ¼41.3 mg/gtissue),whereasthemajoractivecirculatingmetabolite,perillic acid, did not concentrate in the breast tissue. Limonene intervention resulted in a 22% reduction in cyclin D1 expression (P ¼ 0.002) in tumor tissue but minimal changes in tissue Ki67 and cleaved caspase-3 expression. Nosignificant changesin serum leptin,adiponectin, TGF-b1,insulin-like growth factorbinding protein-3 (IGFBP-3), and interleukin-6 (IL-6) levels were observed following limonene intervention. There wasasmallbutstatisticallysignificantpostinterventionincreaseininsulin-likegrowthfactorI(IGF-I)levels. We conclude that limonene distributed extensively to human breast tissue and reduced breast tumor cyclin D1 expression that may lead to cell-cycle arrest and reduced cell proliferation. Furthermore, placebocontrolled clinical trials and translational research are warranted to establish limonene’s role for breast cancer prevention or treatment. Cancer Prev Res; 6(6); 577–84. � 2013 AACR.