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

Uttom Kumar, Yunhui Hu, Nahal Masrour, Marcos Castellanos-Uribe, Alison Harrod, Sean T. May, Simak Ali, Valerie Speirs, R. Charles Coombes, Ernesto Yagüe* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Article number114692
Number of pages15
JournalBiochemical Pharmacology
Volume192
Early online date21 Jul 2021
DOIs
Publication statusPublished - 31 Oct 2021

Keywords

  • FOXC1
  • Galunisertib
  • Metaplastic breast cancer
  • miR-495-3p
  • Multidrug resistance
  • TGF-β

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