Imperial College London
Alternate

ProfessorSimakAli

Faculty of Medicine, Department of Surgery & Cancer

Professor of Molecular Endocrine Oncology
 
 
 
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Contact

 

+44 (0)20 7594 2811simak.ali

 
 
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Location

 

133ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Kumar:2021:10.1016/j.bcp.2021.114692,
author = {Kumar, U and Hu, Y and Masrour, N and Castellanos-Uribe, M and Harrod, A and May, ST and Ali, S and Speirs, V and Charles, Coombes R and Yagüe, E},
doi = {10.1016/j.bcp.2021.114692},
journal = {Biochemical Pharmacology},
pages = {1--15},
title = {MicroRNA-495/TGF-β/FOXC1 axis regulates multidrug resistance in metaplastic breast cancer cells},
url = {http://dx.doi.org/10.1016/j.bcp.2021.114692},
volume = {192},
year = {2021}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Kumar,U
AU  - Hu,Y
AU  - Masrour,N
AU  - Castellanos-Uribe,M
AU  - Harrod,A
AU  - May,ST
AU  - Ali,S
AU  - Speirs,V
AU  - Charles,Coombes R
AU  - Yagüe,E
DO  - 10.1016/j.bcp.2021.114692
EP  - 15
PY  - 2021///
SN  - 0006-2952
SP  - 1
TI  - MicroRNA-495/TGF-β/FOXC1 axis regulates multidrug resistance in metaplastic breast cancer cells
T2  - Biochemical Pharmacology
UR  - http://dx.doi.org/10.1016/j.bcp.2021.114692
UR  - https://www.ncbi.nlm.nih.gov/pubmed/34298004
UR  - https://www.sciencedirect.com/science/article/pii/S0006295221003051?via%3Dihub
UR  - http://hdl.handle.net/10044/1/90676
VL  - 192
ER  -
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