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.
Highlights
The triple-negative breast cancer (TNBC) subtype represents the less frequent (15%) phenotype of breast cancers, despite its low prevalence, it is the target of intense research because of its highly aggressive metastatic nature and very poor prognosis[1,2,3,4]
Doxorubicin treatment produced a viability decrease in all three cell lines: MDA-MB-231 and MDA-MB-468 viability decreased to 60% (p = 0.0024 and p = 0.0017, respectively) and MCF-7 reduced to 70% (p = 0.022)
Gain of miRNAs-449 function produced a statistically significant decrease in cell viability: MDA-MB-231 decreased to 50% (p = 0.004), and MDA-MB-468 and MCF-7 to 60% (p = 0.001 and p = 0.006, respectively)
Summary
The triple-negative breast cancer (TNBC) subtype represents the less frequent (15%) phenotype of breast cancers, despite its low prevalence, it is the target of intense research because of its highly aggressive metastatic nature and very poor prognosis[1,2,3,4] This is mainly due to its lack of specific molecular targets[5], which means that conventional chemotherapy is the main treatment used for these patients. The mechanisms of chemosensitivity and chemoresistance to doxorubicin are still unclear, the study of regulatory pathways and possible specific targets could help optimize patient responses to this treatment In this sense, the role of microRNAs (miRNAs) in cancer regulation and treatment responses are starting to be explored. This could help to improve TNBC treatments or to define more efficient and less toxic alternative therapies
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