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

被引：76

作者：

Tormo, Eduardo ^{[1
,2
]}

Ballester, Sandra ^{[1
]}

Adam-Artigues, Anna ^{[1
]}

Burgues, Octavio ^{[1
,2
,3
]}

Alonso, Elisa ^{[1
,2
,3
]}

Bermejo, Begona ^{[1
,2
]}

Menendez, Silvia ^{[4
]}

Zazo, Sandra ^{[5
]}

Madoz-Gurpide, Juan ^{[5
]}

Rovira, Ana ^{[4
,6
]}

Albanell, Joan ^{[4
,6
,7
]}

Rojo, Federico ^{[5
]}

Lluch, Ana ^{[1
,2
,8
]}

Eroles, Pilar ^{[1
,2
,9
]}

机构：

[1] INCLIVA Biomed Res Inst, Valencia, Spain

[2] Hosp Clin Univ CIBERONC, Oncol & Hematol Dept, Valencia, Spain

[3] Hosp Clin Univ, Pathol Dept, Valencia, Spain

[4] IMIM Hosp Mar Res Inst, Canc Res Program, Barcelona, Spain

[5] IIS Fdn Jimenez Diaz CIBERONC, Pathol Dept, Madrid, Spain

[6] Hosp Mar CIBERONC, Med Oncol Dept, Barcelona, Spain

[7] Univ Pompeu Fabra, Barcelona, Spain

[8] Univ Valencia, Valencia, Spain

[9] COST Act CA15204, Brussels, Belgium

来源：

SCIENTIFIC REPORTS | 2019年 / 9卷 / 1期

关键词：

DNA-DAMAGE RESPONSE; MIR-449A; TARGET; E2F1; PROLIFERATION; CYTOTOXICITY; INVOLVEMENT; ACTIVATION; THERAPY; LOOP;

D O I：

10.1038/s41598-019-41472-y

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：14

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