title: Induction of miRNA-181a by genotoxic treatments promotes chemotherapeutic resistance and metastasis in breast cancer.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Shanghai Medical College, Fudan University, Shanghai.|Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, Shanghai Medical College, Fudan University, Shanghai.
authors.forename: Jixiao
authors.initials: J
authors.lastname: Niu
authors.affiliation: Department of Forensic Medicine, Shanghai Medical College, Fudan University, Shanghai.
authors.forename: Aimin
authors.initials: A
authors.lastname: Xue
authors.affiliation: Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, Shanghai Medical College, Fudan University, Shanghai.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai.|Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai.
authors.forename: Yayun
authors.initials: Y
authors.lastname: Chi
authors.affiliation: Department of Oncology, Shanghai Medical College, Fudan University, Shanghai.|Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai.
authors.forename: Jingyan
authors.initials: J
authors.lastname: Xue
authors.affiliation: Department of Pathology and Laboratory Medicine, Shanghai Medical College, Fudan University, Shanghai.|Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, Shanghai Medical College, Fudan University, Shanghai.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Forensic Medicine, Shanghai Medical College, Fudan University, Shanghai.
authors.forename: Ziqin
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Pathology and Laboratory Medicine, Shanghai Medical College, Fudan University, Shanghai.|Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, Shanghai Medical College, Fudan University, Shanghai.
authors.forename: Meiyun
authors.initials: M
authors.lastname: Fan
authors.affiliation: Department of Pathology and Laboratory Medicine, Shanghai Medical College, Fudan University, Shanghai.|Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, Shanghai Medical College, Fudan University, Shanghai.
authors.forename: Chuan He
authors.initials: CH
authors.lastname: Yang
authors.affiliation: Department of Oncology, Shanghai Medical College, Fudan University, Shanghai.|Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai.
authors.forename: Zhi-Ming
authors.initials: ZM
authors.lastname: Shao
authors.affiliation: Department of Pathology and Laboratory Medicine, Shanghai Medical College, Fudan University, Shanghai.|Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, Shanghai Medical College, Fudan University, Shanghai.
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Pfeffer
authors.affiliation: Department of Oncology, Shanghai Medical College, Fudan University, Shanghai.|Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai.
authors.forename: Jiong
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Pathology and Laboratory Medicine, Shanghai Medical College, Fudan University, Shanghai.|Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, Shanghai Medical College, Fudan University, Shanghai.
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Wu
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009153:Mutagens / Q000633:toxicity*; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D009153:Mutagens; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D051028:bcl-2-Associated X Protein; D004317:Doxorubicin; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1