Role of Polyphenolic Compounds in Chemoprevention of Breast Cancer Stem Cells

Abstract

In the field of integrative oncology, polyphenols have gained attention for their ability to modulate key signaling pathways involved in breast cancer prevention. One noteworthy product, the Polyphenol-Enriched Blueberry Preparation (PEBP), produced by the fermentation of blueberries by the bacterium Rouxiella badensis subsp. acadiensis has demonstrated various beneficial properties, including anti-inflammatory effects and the ability to control cancer stem cells. Cancer Stem Cells (CSCs) are highly tumorigenic cells involved in carcinogenesis and can cause relapses. MicroRNAs (miRNAs) can act as regulators of CSCs, by controlling stemness and invasion. We postulate that PEBP or its polyphenolic components induce specific epigenetic changes by modulating miRNA networks, reducing CSCs, and preventing breast carcinoma. Thus, the overarching aim of this thesis is to better understand the mechanisms underlying the protective effects of the polyphenol-enriched preparation in mitigating breast cancer. The objectives are: 1. To investigate the chemopreventive effects of PEBP on breast cancer stem cell development in cell models and in vivo, as well as to study the involvement of STAT3 and MAPKs signaling pathways 2. Assess the impact of the polyphenol-enriched blueberry preparation on breast cancer by regulating the expression signatures of miRNA involved with cell proliferation, survival, and CSC self-renewal pathways in in vitro experiments. 3. Characterize PEBP and investigate the effect of a subset of its components on miRNA expression. Furthermore, validate the role of those components in regulating the functional behavior of breast cancer stem cells through experiments using a 4T1 animal model. The results have shown a decrease in the formation of CSCs by delaying the development of tumors in vivo, decreasing metastasis to the lungs, and controlling the PTEN/PI3K/AKT axis, a central node in CSC signaling and homeostasis. In addition, several miRNAs associated with different clinical-pathological characteristics of breast cancer were shown to be differentially expressed in CSCs after exposure to PEBP. Notably, the expression of hypoxamir miR-210, associated with a poor prognosis in breast cancer patients, was downregulated, while tumor suppressor miR-145, which prevents metastasis through FOXO1 was over-expressed. The chemopreventive potential of a polyphenolic mixture containing PCA, gallic acid, and catechin, found in PEBP, was also shown to successfully reduce tumour growth and metastasis in our animal model and decrease the presence of stem-like tumour cells by favouring the upregulation of tumour-suppressor miR-145. These findings provide novel evidence in translational medicine, highlighting the effectiveness of a natural epigenetic modulator in chemoprevention by specifically targeting CSCs.