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Int. J. Environ. Res. Public Health 2016, 13(1), 10; doi:10.3390/ijerph13010010

Glyceollin I Reverses Epithelial to Mesenchymal Transition in Letrozole Resistant Breast Cancer through ZEB1

1
College of Pharmacy, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA
2
Tulane University Health Sciences Center, 1430 Tulane Ave, New Orleans, LA 70112, USA
3
Division of Biological and Public Health Sciences, College of Arts and Sciences, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA
4
Division of Mathematical and Physical Sciences, College of Arts and Sciences, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA
5
Southern Regional Research Center, United States Department of Agriculture, New Orleans, LA 70124, USA
6
Division of Basic Sciences, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, 1415 S. Martin L. King Jr. Blvd., Tallahassee, FL 32307, USA
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editors: Mark Edberg, Barbara E. Hayes, Valerie Montgomery Rice and Paul B. Tchounwou
Received: 7 August 2015 / Revised: 20 August 2015 / Accepted: 24 August 2015 / Published: 22 December 2015
View Full-Text   |   Download PDF [3613 KB, uploaded 22 December 2015]   |  

Abstract

Although aromatase inhibitors are standard endocrine therapy for postmenopausal women with early-stage metastatic estrogen-dependent breast cancer, they are limited by the development of drug resistance. A better understanding of this process is critical towards designing novel strategies for disease management. Previously, we demonstrated a global proteomic signature of letrozole-resistance associated with hormone-independence, enhanced cell motility and implications of epithelial mesenchymal transition (EMT). Letrozole-resistant breast cancer cells (LTLT-Ca) were treated with a novel phytoalexin, glyceollin I, and exhibited morphological characteristics synonymous with an epithelial phenotype and decreased proliferation. Letrozole-resistance increased Zinc Finger E-Box Binding Homeobox 1 (ZEB1) expression (4.51-fold), while glyceollin I treatment caused a −3.39-fold reduction. Immunofluorescence analyses resulted of glyceollin I-induced increase and decrease in E-cadherin and ZEB1, respectively. In vivo studies performed in ovariectomized, female nude mice indicated that glyceollin treated tumors stained weakly for ZEB1 and N-cadherin and strongly for E-cadherin. Compared to letrozole-sensitive cells, LTLT-Ca cells displayed enhanced motility, however in the presence of glyceollin I, exhibited a 68% and 83% decrease in invasion and migration, respectively. These effects of glyceollin I were mediated in part by inhibition of ZEB1, thus indicating therapeutic potential of glyceollin I in targeting EMT in letrozole resistant breast cancer. View Full-Text
Keywords: letrozole resistance; epithelial mesenchymal transition; breast cancer; phytochemicals; aromatase inhibitors; metastasis letrozole resistance; epithelial mesenchymal transition; breast cancer; phytochemicals; aromatase inhibitors; metastasis
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Carriere, P.P.; Llopis, S.D.; Naiki, A.C.; Nguyen, G.; Phan, T.; Nguyen, M.M.; Preyan, L.C.; Yearby, L.; Pratt, J.; Burks, H.; Davenport, I.R.; Nguyen, T.A.; Parker-Lemieux, K.; Payton-Stewart, F.; Williams, C.C.; Boué, S.M.; Burow, M.E.; Collins-Burow, B.; Hilliard, A.; Davidson, A.M.; Tilghman, S.L. Glyceollin I Reverses Epithelial to Mesenchymal Transition in Letrozole Resistant Breast Cancer through ZEB1. Int. J. Environ. Res. Public Health 2016, 13, 10.

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