Inhibition of triple-negative breast cancer (TNBC) and breast cancer stem cells (bCSC) by caffeic acid phenethyl ester (CAPE).

Abstract

e13587 Background: TNBC is a high mortality disease with a paucity of therapeutics. Our preclinical data used CAPE, a main component of propolis, a honeybee product credited with antiinflammatory, antioxidant, and antitumor properties. CAPE, which is innocuous to normal human mammary epithelial cells, inhibits growth of MDA-MB-231 (231) cells, MDR gene expression, NF-kB, EGFR and VEGF. We used 231 cells, a model of human TNBC, to show that CAPE can combat TNBC as a therapeutic, and/or adjuvant to chemotherapeutic drugs like Taxol. Cancer stem cells (CSC) are implicated in tumor metastasis and recurrence, thus, agents impairing their self-renewal, could be invaluable as novel cancer therapeutics. We show that CAPE could be such an agent, because it inhibits CSC growth and self renewal. We propose that the mechanism for this inhibition is due to the induction of CSC apoptosis. Methods: Nude mice bearing 231 xenografts were fed CAPE diets and/or treated topically with CAPE and tumors measured 2x/week. bCSC were isolated from 231 cells and xenografts and propagated as mammospheres. Cell growth was analyzed using MTT and cell cycle by flow cytometry. Apoptosis was determined by co-staining of bCSC with Annexin V and propidium iodide. Results: Dietary CAPE significantly inhibited growth of 231 xenografts. Subsequent topical CAPE treatment further decreased tumor volume. 231 cells contain bCSC thought to be responsible for metastasis and recurrence. CAPE decreased bCSC clonal growth and inhibited their self-renewal and progenitors as evidenced by decreased growth in soft agar after pretreatment with CAPE. Further, CAPE induced apoptosis of bCSC in a dose-dependent manner up to 20μM CAPE, but apoptosis was decreased at 40μM. Conclusions: Our results strongly suggest that low doses of CAPE reduce TNBC growth by oral and/or topical routes, most likely by suppressing bCSC self-renewal at least partly by inducing apoptosis. CAPE could be a powerful inhibitor of CSC-mediated recurrence of aggressive types of breast cancer including TNBC. Research is ongoing to delineate in detail the mechanism(s) contributing to CSC inhibition by CAPE as it relates to the changes in CSC characteristics and differentiation. No significant financial relationships to disclose.