title: Mechanism of Breast Cancer Preventive Action of Pomegranate: Disruption of Estrogen Receptor and Wnt/β-Catenin Signaling Pathways.
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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH 44272, USA. animandal@rediffmail.com.
authors.forename: Animesh
authors.initials: A
authors.lastname: Mandal
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Larkin Health Sciences Institute, 18301 N. Miami Avenue, Miami, FL 33169, USA. abishayee@ULarkin.org.
authors.forename: Anupam
authors.initials: A
authors.lastname: Bishayee
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism; D018890:Chemoprevention / Q000379:methods; D015536:Down-Regulation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D029561:Lythraceae / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D016588:Anticarcinogenic Agents; D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen; D051153:Wnt Proteins; D051176:beta Catenin; D015127:9,10-Dimethyl-1,2-benzanthracene
keywords: DMBA; cyclin D1; estrogen receptors; mammary tumorigenesis; pomegranate (Punica granatum L.); β-catenin