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MicroRNA-495/TGF-β/FOXC1 axis regulates multidrug resistance in metaplastic breast cancer cells

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Title: MicroRNA-495/TGF-β/FOXC1 axis regulates multidrug resistance in metaplastic breast cancer cells
Authors: Kumar, U
Hu, Y
Masrour, N
Castellanos-Uribe, M
Harrod, A
May, ST
Ali, S
Speirs, V
Charles Coombes, R
Yagüe, E
Item Type: Journal Article
Abstract: Triple-negative metaplastic breast carcinoma (MBC) poses a significant treatment challenge due to lack of targeted therapies and chemotherapy resistance. We isolated a novel MBC cell line, BAS, which showed a molecular and phenotypic profile different from the only other metaplastic cell model, HS578T cells. To gain insight behind chemotherapeutic resistance, we generated doxorubicin (HS-DOX, BAS-DOX) and paclitaxel (HS-TX, BAS-TX) resistant derivatives of both cell lines. Drug sensitivity assays indicated a truly multidrug resistant (MDR) phenotype. Both BAS-DOX and BAS-TX showed up-regulation of FOXC1 and its experimental down-regulation re-sensitized cells to doxorubicin and paclitaxel. Experimental modulation of FOXC1 expression in MCF-7 and MDA-MB-231 cells corroborated its role in MDR. Genome-wide expression analyses identified gene expression signatures characterized by up-regulation of TGFB2, which encodes cytokine TGF-β2, in both BAS-DOX and BAS-TX cells. Pharmacological inhibition of the TGF-β pathway with galunisertib led to down-regulation of FOXC1 and increase in drug sensitivity in both BAS-DOX and BAS-TX cells. MicroRNA (miR) expression analyses identified high endogenous miR-495-3p levels in BAS cells that were downregulated in both BAS MDR cells. Transient expression of miR-495-3p mimic in BAS-DOX and BAS-TX cells caused downregulation of TGFB2 and FOXC1 and re-sensitized cells to doxorubicin and paclitaxel, whereas miR-495-3p inhibition in BAS cells led to increase in resistance to both drugs and up-regulation of TGFB2 and FOXC1. Together, these data suggest interplay between miR-495-3p, TGF-β2 and FOXC1 regulating MDR in MBC and open the exploration of novel therapeutic strategies.
Issue Date: 21-Jul-2021
Date of Acceptance: 15-Jul-2021
URI: http://hdl.handle.net/10044/1/90676
DOI: 10.1016/j.bcp.2021.114692
ISSN: 0006-2952
Publisher: Elsevier
Start Page: 1
End Page: 15
Journal / Book Title: Biochemical Pharmacology
Volume: 192
Copyright Statement: © 2021 Elsevier Inc. All rights reserved. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence http://creativecommons.org/licenses/by-nc-nd/4.0/
Sponsor/Funder: Commonwealth Scholarship Commission
Funder's Grant Number: BDCS-2017-61
Keywords: FOXC1
Galunisertib
Metaplastic breast cancer
Multidrug resistance
TGF-β
miR-495-3p
FOXC1
Galunisertib
Metaplastic breast cancer
Multidrug resistance
TGF-β
miR-495-3p
Pharmacology & Pharmacy
0601 Biochemistry and Cell Biology
1115 Pharmacology and Pharmaceutical Sciences
Publication Status: Published
Conference Place: England
Embargo Date: 2022-07-20
Article Number: 114692
Online Publication Date: 2021-07-21
Appears in Collections:Department of Surgery and Cancer
Faculty of Medicine



This item is licensed under a Creative Commons License Creative Commons