The role of microRNA-128a in regulating TGFbeta signaling in letrozole-resistant breast cancer cells.
Resistance to endocrine therapy agents has presented a clinical obstacle in the treatment of hormone-dependent breast cancer. Our laboratory has initiated a study of microRNA regulation of signaling pathways that may result in breast cancer progression on aromatase inhibitors (AI). Microarray analysis of hormone refractory cell lines identified 115 differentially regulated microRNAs, of which 49 microRNAs were believed to be hormone-responsive. A group of microRNAs were inversely expressed in the AI-resistant lines versus LTEDaro and tamoxifen-resistant. We focused our work on hsa-miR-128a which was hormone-responsive and selectively up-regulated in the letrozole-resistant cell lines. Human miR-128a was predicted to target the TGFβ signaling pathway and indeed sensitivity to TGFβ was compromised in the letrozole-resistant cells, as compared to parental MCF-7aro. Human miR-128a was shown to negatively target TGFβRI protein expression by binding to the 3'UTR region of the gene. Inhibition of endogenous miR-128a resulted in resensitization of the letrozole-resistant lines to TGFβ growth inhibitory effects. These data suggest that the hormone-responsive miR-128a can modulate TGFβ signaling and survival of the letrozole-resistant cell lines. To our knowledge, this is the first study to address the role of microRNA regulation as well as TGFβ signaling in AI-resistant breast cancer cell lines. We believe that in addition to estrogen-modulation of gene expression, hormone-regulated microRNAs may provide an additional level of post-transcriptional regulation of signaling pathways critically involved in breast cancer progression and AI-resistance.
Masri
Selma
S
Division of Tumor Cell Biology, Beckman Research Institute of the City of Hope, 1500 E Duarte Road, Duarte, CA 91010, USA.
Liu
Zheng
Z
Phung
Sheryl
S
Wang
Emily
E
Yuan
Yate-Ching
YC
Chen
Shiuan
S
D020413:3' Untranslated Regions; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004958:Estradiol / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D000077289:Letrozole; D035683:MicroRNAs / Q000378:metabolism*; D008969:Molecular Sequence Data; D009570:Nitriles / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013739:Testosterone / Q000378:metabolism; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology*
D020413:3' Untranslated Regions; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; C545189:MIRN128 microRNA, human; D035683:MicroRNAs; D009570:Nitriles; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014230:Triazoles; D013739:Testosterone; D004958:Estradiol; D000077289:Letrozole; D001141:Aromatase; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I