The miRNA-449 family mediates doxorubicin resistance in triple-negative breast cancer by regulating cell cycle factors

Autores de INCLIVA

• Eduardo Tormo Martin

  Autor

• Sandra Ballester Garcia

  Autor

• Anna Adam Artigues

  Autor

• Octavio Burgues Gasion

  Autor

• Elisa Alonso Yuste

  Autor

• 

  Begoña Bermejo De Las Heras

  Autor

• 

  Ana Lluch Hernández

  Autor

• 

  Pilar Eroles Asensio

  Autor

Participantes ajenos a INCLIVA

• Menendez, S
• Zazo, S
• Madoz-Gurpide, J
• Rovira, A
• Albanell, J
• Rojo, F

Grupos y Plataformas de I+D+i

• Grupo de Investigación en Biología en Cáncer de mama

  

  Leading Researcher

  Pilar Eroles Asensio

Abstract

The mechanisms of chemotherapy resistance in triple negative breast cancer remain unclear, and so, new molecules which might mediate this resistance could optimize treatment response. Here we analyzed the involvement of the miRNA-449 family in the response to doxorubicin. The cell viability, cell-cycle phases, and the expression of in silico target genes and proteins of sensitive/resistant triple negative breast cancer cell lines were evaluated in response to doxorubicin treatment and after gain/loss of miRNAs-449 function achieved by transient transfection. Triple negative breast cancer patients were selected for ex vivo experiments and to evaluate gene and miRNAs expression changes after treatment, as well as survival analysis by Kaplan-Meier. Doxorubicin treatment upregulated miRNAs-449 and DNA-damage responder factors E2F1 and E2F3 in triple negative breast cancer sensitive breast cancer cells, while expression remained unaltered in resistant ones. In vitro overexpression of miRNAs-449 sensitized cells to the treatment and significantly reduced the resistance to doxorubicin. These changes showed also a strong effect on cell cycle regulation. Finally, elevated levels of miRNA-449a associated significantly with better survival in chemotherapy-treated triple negative breast cancer patients. These results reveal for the first time the involvement of the miRNA-449 family in doxorubicin resistance and their predictive and prognostic value in triple negative breast cancer patients.

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