Abstract
Scientific evidence supports the early deregulation of epigenetic profiles during breast carcinogenesis. Research shows that cellular transformation, carcinogenesis, and stemness maintenance are regulated by epigenetic-specific changes that involve microRNAs (miRNAs). Dietary bioactive compounds such as blueberry polyphenols may modulate susceptibility to breast cancer by the modulation of CSC survival and self-renewal pathways through the epigenetic mechanism, including the regulation of miRNA expression. Therefore, the current study aimed to assay the effect of polyphenol enriched blueberry preparation (PEBP) or non-fermented blueberry juice (NBJ) on the modulation of miRNA signature and the target proteins associated with different clinical-pathological characteristics of breast cancer such as stemness, invasion, and chemoresistance using breast cancer cell lines. To this end, 4T1 and MB-MDM-231 cell lines were exposed to NBJ or PEBP for 24 h. miRNA profiling was performed in breast cancer cell cultures, and RT-qPCR was undertaken to assay the expression of target miRNA. The expression of target proteins was examined by Western blotting. Profiling of miRNA revealed that several miRNAs associated with different clinical-pathological characteristics were differentially expressed in cells treated with PEBP. The validation study showed significant downregulation of oncogenic miR-210 expression in both 4T1 and MDA-MB-231 cells exposed to PEBP. In addition, expression of tumor suppressor miR-145 was significantly increased in both cell lines treated with PEBP. Western blot analysis showed a significant increase in the relative expression of FOXO1 in 4T1 and MDA-MB-231 cells exposed to PEBP and in MDA-MB-231 cells exposed to NBJ. Furthermore, a significant decrease was observed in the relative expression of N-RAS in 4T1 and MDA-MB-231 cells exposed to PEBP and in MDA-MB-231 cells exposed to NBJ. Our data indicate a potential chemoprevention role of PEBP through the modulation of miRNA expression, particularly miR-210 and miR-145, and protection against breast cancer development and progression. Thus, PEBP may represent a source for novel chemopreventative agents against breast cancer.
Highlights
Breast cancer is the world’s most commonly diagnosed cancer, making up 11.7% of total cases in 2020
Given the significant role of epigenetic regulation in breast cancer formation and, as we have previously shown in the repression of breast cancer stem cells (CSCs) by polyphenol enriched blueberry preparation (PEBP) [22], the current study aimed to investigate the possible mechanism of action of PEBP against the development of breast cancer through the regulation of the miRNAs expression signature involved in cell proliferation, survival, and CSC self-renewal pathways in vitro using breast cancer cell lines
The dose–response curve showed a significant effect of PEBP ranging from 40 to 200 μM gallic acid equivalent (GAE)
Summary
Breast cancer is the world’s most commonly diagnosed cancer, making up 11.7% of total cases in 2020. Reproductive and hormonal factors, as well as lifestyle risk factors such as alcohol intake, obesity, and physical inactivity, contribute to breast cancer pathogenesis [1]. Histological and molecular subtypes are used to classify breast cancer. Molecular subtype classification is based on the presence or lack of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor-2 (HER2) [2]. Triple-Negative is an aggressive subtype of breast cancer and because of the absence of estrogen, progesterone, and HER2 receptor expression, no targeted therapy has been developed for this subtype therapy [3]. Different targeted therapies, such as targeting epigenetic changes associated with cancer, have been developed to increase the efficacy of cancer treatment [2]
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