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

5 Citations (Scopus)


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
Early online date21 Jul 2021
Publication statusPublished - 31 Oct 2021


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


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