Mechanism of Breast Cancer Preventive Action of Pomegranate: Disruption of Estrogen Receptor and Wnt/β-Catenin Signaling Pathways.

Animesh Mandal,Anupam Bishayee

doi:10.3390/molecules201219853

Animesh Mandal, Anupam Bishayee

Open Access

https://doi.org/10.3390/molecules201219853

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Abstract

A pomegranate emulsion (PE), containing various bioactive phytochemicals, has recently been found to exert substantial chemopreventive effect against 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumorigenesis in rats via antiproliferative and proapoptotic actions. Nevertheless, the underlying mechanisms of action are not completely understood. The present study was designed to investigate the effects of PE treatment on intratumor expression of estrogen receptor (ER)-α, ER-β,β-catenin and cyclin D1 during DMBA rat mammary carcinogenesis. Mammary tumor sections were harvested from a chemopreventive study in which PE (0.2, 1.0 and 5.0 g/kg) exhibited inhibition of mammary tumorigenesis in a dose-response manner. The expressions of ER-α, ER-β, β-catenin and cyclin D1 were analyzed by immunohistochemical techniques. PE downregulated the expression of intratumor ER-α and ER-β and lowered ER-α:ER-β ratio. PE also decreased the expression, cytoplasmic accumulation, and nuclear translocation of β-catenin, an essential transcriptional cofactor for Wnt signaling. Moreover, PE suppressed the expression of cell growth regulatory protein cyclin D1, which is a downstream target for both ER and Wnt signaling. Our current results in conjunction with our previous findings indicate that concurrent disruption of ER and Wnt/β-catenin signaling pathways possibly contributes to antiproliferative and proapoptotic effects involved in PE-mediated chemoprevention of DMBA-inflicted rat mammary tumorigenesis.

Highlights

Breast cancer is the most common cancer among women and the second leading cause of cancer-associated deaths in humans worldwide
Since down-modulation of Wnt/β-catenin signaling has been associated with inhibition of cellular proliferation and induction of apoptosis [73], suppression of constitutive activation of Wnt/β-catenin signaling appears to be a possible mechanism of pomegranate emulsion (PE)-mediated inhibition of cell proliferation and escalation of apoptosis in DMBA-initiated mammary tumorigenesis in rats as we reported earlier [50]
Based on results presented here, we conclude that PE abrogates the expression of estrogen receptor (ER)-α and ER-β during DMBA-inflicted mammary tumorigenesis in rats

Summary

Introduction

Breast cancer is the most common cancer among women and the second leading cause of cancer-associated deaths in humans worldwide. According to GLOBOCAN 2012 [1], 522,000 women died of breast cancer in both developed and developing countries in 2012. In 2015, approximately 232,000 new breast cancer cases and about 40,000 deaths are estimated to occur in women in the United States [2]. Breast cancer occurs in men with very less frequency compared to women [3]. There are several acquired risk factors for breast cancer which include early onset of menstruation, not having children, delayed birth of a first child, short duration of breast feeding, late menopause, use of hormone replacement therapy, aging, obesity, diabetes, alcohol consumption and circadian disruption [6,7,8,9,10,11,12,13]

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