Novel Diphenylamine Analogs Induce Mesenchymal to Epithelial Transition in Triple Negative Breast Cancer

Epithelial to mesenchymal transition (EMT) is a cellular program that converts non-motile epithelial cells into invasive mesenchymal cells. EMT is implicated in cancer metastasis, chemo-resistance, cancer progression, and generation of cancer stem cells (CSCs). Inducing mesenchymal to epithelial tra...

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Main Authors: Akshita B. Bhatt, Mohit Gupta, Van T. Hoang, Suravi Chakrabarty, Thomas D. Wright, Steven Elliot, Ishveen K. Chopra, Darlene Monlish, Katie Anna, Matthew E. Burow, Jane E. Cavanaugh, Patrick T. Flaherty
Format: Article
Language:English
Published: Frontiers Media S.A. 2019-07-01
Series:Frontiers in Oncology
Subjects:
Online Access:https://www.frontiersin.org/article/10.3389/fonc.2019.00672/full
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author Akshita B. Bhatt
Mohit Gupta
Van T. Hoang
Suravi Chakrabarty
Thomas D. Wright
Steven Elliot
Ishveen K. Chopra
Darlene Monlish
Katie Anna
Matthew E. Burow
Jane E. Cavanaugh
Patrick T. Flaherty
author_facet Akshita B. Bhatt
Mohit Gupta
Van T. Hoang
Suravi Chakrabarty
Thomas D. Wright
Steven Elliot
Ishveen K. Chopra
Darlene Monlish
Katie Anna
Matthew E. Burow
Jane E. Cavanaugh
Patrick T. Flaherty
author_sort Akshita B. Bhatt
collection DOAJ
description Epithelial to mesenchymal transition (EMT) is a cellular program that converts non-motile epithelial cells into invasive mesenchymal cells. EMT is implicated in cancer metastasis, chemo-resistance, cancer progression, and generation of cancer stem cells (CSCs). Inducing mesenchymal to epithelial transition (MET), the reverse phenomenon of EMT, is proposed as a novel strategy to target triple negative and tamoxifen-resistant breast cancer. Triple negative breast cancer (TNBC) is characterized by the loss of hormone receptors, a highly invasive mesenchymal phenotype, and a lack of targeted therapy. Estrogen receptor-positive breast cancer can be targeted by tamoxifen, an ER antagonist. However, these cells undergo EMT over the course of treatment and develop resistance. Thus, there is an urgent need to develop therapeutic interventions to target these aggressive cancers. In this study, we examined the role of novel diphenylamine analogs in converting the mesenchymal phenotype of MDA-MB-231 TNBC cells to a lesser aggressive epithelial phenotype. Using analog-based drug design, a series of diphenylamine analogs were synthesized and initially evaluated for their effect on E-cadherin protein expression and changes incell morphology, which was quantified by measuring the spindle index (SI) value. Selected compound 1 from this series increases the expression of E-cadherin, a primary marker for epithelial cells, and decreases the mesenchymal markers SOX2, ZEB1, Snail, and vimentin. The increase in epithelial markers and the decrease in mesenchymal markers are consistent with a phenotypic switch from spindle-like morphology to cobblestone-like morphology. Furthermore, Compound 1 decreases spheroid viability, cell migration, and cell proliferation in triple negative BT-549 and tamoxifen-resistant MCF-7 breast cancer cells.
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spelling doaj.art-df10d63f800f4b54b1e02ff11056280c2022-12-22T01:59:14ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2019-07-01910.3389/fonc.2019.00672467816Novel Diphenylamine Analogs Induce Mesenchymal to Epithelial Transition in Triple Negative Breast CancerAkshita B. Bhatt0Mohit Gupta1Van T. Hoang2Suravi Chakrabarty3Thomas D. Wright4Steven Elliot5Ishveen K. Chopra6Darlene Monlish7Katie Anna8Matthew E. Burow9Jane E. Cavanaugh10Patrick T. Flaherty11Division of Pharmacology, School of Pharmacy, Duquesne University, Pittsburgh, PA, United StatesDivision of Medicinal Chemistry, School of Pharmacy, Duquesne University, Pittsburgh, PA, United StatesDepartment of Medicine-Section of Hematology and Medical Oncology, Tulane University, New Orleans, LA, United StatesDivision of Medicinal Chemistry, School of Pharmacy, Duquesne University, Pittsburgh, PA, United StatesDivision of Pharmacology, School of Pharmacy, Duquesne University, Pittsburgh, PA, United StatesDepartment of Medicine-Section of Hematology and Medical Oncology, Tulane University, New Orleans, LA, United StatesDivision of Medicinal Chemistry, School of Pharmacy, Duquesne University, Pittsburgh, PA, United StatesDivision of Pharmacology, School of Pharmacy, Duquesne University, Pittsburgh, PA, United StatesDivision of Pharmacology, School of Pharmacy, Duquesne University, Pittsburgh, PA, United StatesDepartment of Medicine-Section of Hematology and Medical Oncology, Tulane University, New Orleans, LA, United StatesDivision of Pharmacology, School of Pharmacy, Duquesne University, Pittsburgh, PA, United StatesDivision of Medicinal Chemistry, School of Pharmacy, Duquesne University, Pittsburgh, PA, United StatesEpithelial to mesenchymal transition (EMT) is a cellular program that converts non-motile epithelial cells into invasive mesenchymal cells. EMT is implicated in cancer metastasis, chemo-resistance, cancer progression, and generation of cancer stem cells (CSCs). Inducing mesenchymal to epithelial transition (MET), the reverse phenomenon of EMT, is proposed as a novel strategy to target triple negative and tamoxifen-resistant breast cancer. Triple negative breast cancer (TNBC) is characterized by the loss of hormone receptors, a highly invasive mesenchymal phenotype, and a lack of targeted therapy. Estrogen receptor-positive breast cancer can be targeted by tamoxifen, an ER antagonist. However, these cells undergo EMT over the course of treatment and develop resistance. Thus, there is an urgent need to develop therapeutic interventions to target these aggressive cancers. In this study, we examined the role of novel diphenylamine analogs in converting the mesenchymal phenotype of MDA-MB-231 TNBC cells to a lesser aggressive epithelial phenotype. Using analog-based drug design, a series of diphenylamine analogs were synthesized and initially evaluated for their effect on E-cadherin protein expression and changes incell morphology, which was quantified by measuring the spindle index (SI) value. Selected compound 1 from this series increases the expression of E-cadherin, a primary marker for epithelial cells, and decreases the mesenchymal markers SOX2, ZEB1, Snail, and vimentin. The increase in epithelial markers and the decrease in mesenchymal markers are consistent with a phenotypic switch from spindle-like morphology to cobblestone-like morphology. Furthermore, Compound 1 decreases spheroid viability, cell migration, and cell proliferation in triple negative BT-549 and tamoxifen-resistant MCF-7 breast cancer cells.https://www.frontiersin.org/article/10.3389/fonc.2019.00672/fullMETEMTphenotypic switchmesenchymalTNBCMAPK
spellingShingle Akshita B. Bhatt
Mohit Gupta
Van T. Hoang
Suravi Chakrabarty
Thomas D. Wright
Steven Elliot
Ishveen K. Chopra
Darlene Monlish
Katie Anna
Matthew E. Burow
Jane E. Cavanaugh
Patrick T. Flaherty
Novel Diphenylamine Analogs Induce Mesenchymal to Epithelial Transition in Triple Negative Breast Cancer
Frontiers in Oncology
MET
EMT
phenotypic switch
mesenchymal
TNBC
MAPK
title Novel Diphenylamine Analogs Induce Mesenchymal to Epithelial Transition in Triple Negative Breast Cancer
title_full Novel Diphenylamine Analogs Induce Mesenchymal to Epithelial Transition in Triple Negative Breast Cancer
title_fullStr Novel Diphenylamine Analogs Induce Mesenchymal to Epithelial Transition in Triple Negative Breast Cancer
title_full_unstemmed Novel Diphenylamine Analogs Induce Mesenchymal to Epithelial Transition in Triple Negative Breast Cancer
title_short Novel Diphenylamine Analogs Induce Mesenchymal to Epithelial Transition in Triple Negative Breast Cancer
title_sort novel diphenylamine analogs induce mesenchymal to epithelial transition in triple negative breast cancer
topic MET
EMT
phenotypic switch
mesenchymal
TNBC
MAPK
url https://www.frontiersin.org/article/10.3389/fonc.2019.00672/full
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