title: Glyceollin I Reverses Epithelial to Mesenchymal Transition in Letrozole Resistant Breast Cancer through ZEB1.
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.
authors.affiliation: College of Pharmacy, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA. pcarriere@msm.edu.
authors.forename: Patrick P
authors.initials: PP
authors.lastname: Carriere
authors.affiliation: College of Pharmacy, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA. sllopis@xula.edu.
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Llopis
authors.affiliation: College of Pharmacy, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA. acnaiki@gmail.com.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Naiki
authors.affiliation: College of Pharmacy, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA. gi.nguye@gmail.com.
authors.forename: Gina
authors.initials: G
authors.lastname: Nguyen
authors.affiliation: College of Pharmacy, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA. tphan0917@gmail.com.
authors.forename: Tina
authors.initials: T
authors.lastname: Phan
authors.affiliation: College of Pharmacy, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA. marym.nguy@gmail.com.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Nguyen
authors.affiliation: College of Pharmacy, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA. lynezpreyan@gmail.com.
authors.forename: Lynez C
authors.initials: LC
authors.lastname: Preyan
authors.affiliation: College of Pharmacy, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA. lyearby@xula.edu.
authors.forename: Letitia
authors.initials: L
authors.lastname: Yearby
authors.affiliation: College of Pharmacy, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA. jpratt1@xula.edu.
authors.forename: Jamal
authors.initials: J
authors.lastname: Pratt
authors.affiliation: Tulane University Health Sciences Center, 1430 Tulane Ave, New Orleans, LA 70112, USA. hburks@tulane.edu.
authors.forename: Hope
authors.initials: H
authors.lastname: Burks
authors.affiliation: Division of Biological and Public Health Sciences, College of Arts and Sciences, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA. idavenpo@xula.edu.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Davenport
authors.affiliation: College of Pharmacy, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA. tnguye71@xula.edu.
authors.forename: Thu A
authors.initials: TA
authors.lastname: Nguyen
authors.affiliation: College of Pharmacy, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA. kparker1@xula.edu.
authors.forename: KiTani
authors.initials: K
authors.lastname: Parker-Lemieux
authors.affiliation: Division of Mathematical and Physical Sciences, College of Arts and Sciences, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA. flpayton@xula.edu.
authors.forename: Florastina
authors.initials: F
authors.lastname: Payton-Stewart
authors.affiliation: College of Pharmacy, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA. cwillia35@xula.edu.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Williams
authors.affiliation: Southern Regional Research Center, United States Department of Agriculture, New Orleans, LA 70124, USA. steve.boue@ars.usda.gov.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Boué
authors.affiliation: Tulane University Health Sciences Center, 1430 Tulane Ave, New Orleans, LA 70112, USA. mburow@tulane.edu.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Burow
authors.affiliation: Tulane University Health Sciences Center, 1430 Tulane Ave, New Orleans, LA 70112, USA. bcollins1@tulane.edu.
authors.forename: Bridgette
authors.initials: B
authors.lastname: Collins-Burow
authors.affiliation: Division of Basic Sciences, College of Pharmacy and Pharmaceutical Sciences, Florida A&amp;M University, 1415 S. Martin L. King Jr. Blvd., Tallahassee, FL 32307, USA. aaron.hilliard@famu.edu.
authors.forename: Aaron
authors.initials: A
authors.lastname: Hilliard
authors.affiliation: Division of Basic Sciences, College of Pharmacy and Pharmaceutical Sciences, Florida A&amp;M University, 1415 S. Martin L. King Jr. Blvd., Tallahassee, FL 32307, USA. michael.davidson@famu.edu.
authors.forename: A Michael
authors.initials: AM
authors.lastname: Davidson
authors.affiliation: Division of Basic Sciences, College of Pharmacy and Pharmaceutical Sciences, Florida A&amp;M University, 1415 S. Martin L. King Jr. Blvd., Tallahassee, FL 32307, USA. syreeta.tilghman@famu.edu.
authors.forename: Syreeta L
authors.initials: SL
authors.lastname: Tilghman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000503:physiopathology*; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D006801:Humans; D000077289:Letrozole; D051379:Mice; D008819:Mice, Nude; D009570:Nitriles / Q000378:metabolism* / Q000627:therapeutic use; D036343:Pterocarpans / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014230:Triazoles / Q000378:metabolism* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D009570:Nitriles; D036343:Pterocarpans; D014157:Transcription Factors; D014230:Triazoles; C017343:glyceollin; D000077289:Letrozole
keywords: aromatase inhibitors; breast cancer; epithelial mesenchymal transition; letrozole resistance; metastasis; phytochemicals