Induction of miRNA-181a by genotoxic treatments promotes chemotherapeutic resistance and metastasis in breast cancer

J. Niu, A. Xue, Y. Chi, J. Xue, Wei Wang, Z. Zhao, Meiyun Fan, Chuan Yang, Z. M. Shao, Lawrence Pfeffer, J. Wu, Zhaohui Wu

Research output: Contribution to journalArticle

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Abstract

Acquired therapeutic resistance is the major drawback to effective systemic therapies for cancers. Aggressive triple-negative breast cancers (TNBC) develop resistance to chemotherapies rapidly, whereas the underlying mechanisms are not completely understood. Here we show that genotoxic treatments significantly increased the expression of miR-181a in TNBC cells, which enhanced TNBC cell survival and metastasis upon Doxorubicin treatment. Consistently, high miR-181a level associated with poor disease free survival and overall survival after treatments in breast cancer patients. The upregulation of miR-181a was orchestrated by transcription factor STAT3 whose activation depended on NF-κB-mediated IL-6 induction in TNBC cells upon genotoxic treatment. Intriguingly, activated STAT3 not only directly bound to MIR181A1 promoter to drive transcription but also facilitated the recruitment of MSK1 to the same region where MSK1 promoted a local active chromatin state by phosphorylating histone H3. We further identified BAX as a direct functional target of miR-181a, whose suppression decreased apoptosis and increased invasion of TNBC cells upon Dox treatment. These results were further confirmed by evidence that suppression of miR-181a significantly enhanced therapeutic response and reduced lung metastasis in a TNBC orthotopic model. Collectively, our data suggested that miR-181a induction had a critical role in promoting therapeutic resistance and aggressive behavior of TNBC cells upon genotoxic treatment. Antagonizing miR-181a may serve as a promising strategy to sensitize TNBC cells to chemotherapy and mitigate metastasis.

Original languageEnglish (US)
Pages (from-to)1302-1313
Number of pages12
JournalOncogene
Volume35
Issue number10
DOIs
StatePublished - Mar 10 2016

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Triple Negative Breast Neoplasms
MicroRNAs
Breast Neoplasms
Neoplasm Metastasis
Therapeutics
Drug Therapy
STAT3 Transcription Factor
Histones
Doxorubicin
Disease-Free Survival
Chromatin
Interleukin-6
Cell Survival
Up-Regulation
Apoptosis
Lung
Survival

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Induction of miRNA-181a by genotoxic treatments promotes chemotherapeutic resistance and metastasis in breast cancer. / Niu, J.; Xue, A.; Chi, Y.; Xue, J.; Wang, Wei; Zhao, Z.; Fan, Meiyun; Yang, Chuan; Shao, Z. M.; Pfeffer, Lawrence; Wu, J.; Wu, Zhaohui.

In: Oncogene, Vol. 35, No. 10, 10.03.2016, p. 1302-1313.

Research output: Contribution to journalArticle

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