title: Coordinated regulation of β-tubulin isotypes and epithelial-to-mesenchymal transition protein ZEB1 in breast cancer cells.
abstract: The regulation of β-tubulin isotypes, the primary targets for antimitotic chemotherapeutic drugs like taxanes, has implications for drug response and drug resistance. Over the past 15 years, micro-RNAs have been studied widely as regulators of mRNA levels. For example, the tumor suppressor miR-200c was shown in cell culture to target mesenchymal genes, including ZEB1 [ Cochrane ( 2009 ) Mol. Cancer Ther. 8 ( 5 ), 1055 - 1066 ]. In that work, exogenous miR-200c was also shown to reduce β-tubulin class III, one of its predicted targets. Furthermore, decreased miR-200c and increased β-tubulin class III were associated with poor outcomes for ovarian cancer patients [ Cittelly , D.M. ( 2012 ) Mol. Cancer Ther. 11 ( 12 ), 2556 - 2565 ]. Because miR-200c targets the epithelial-to-mesenchymal inducer ZEB1, we wanted to know whether changes in ZEB1 parallel β-tubulin isotype changes, implicating β-tubulin isotypes in ZEB1-associated cell survival pathways. We found coordinated positive feedback regulation of mRNA for ZEB1 and β-tubulin isotype classes I, III, and IVB in MDA-MB-231 breast cancer cells, commonly used as a model for triple-negative breast cancers. Low levels of paclitaxel (40 nM) were found to significantly reduce mRNA levels for these tubulin genes along with a 2-3-fold increase in miR-200c. ZEB1 silencing also reduced β-tubulin isotype classes I, III, and IVB mRNA, whereas upregulation of ZEB1 was associated with increases in these isotype classes. Our work indicates that paclitaxel-induced reduction of ZEB1 and β-tubulin isotypes are, in part, due to increased activity of miR-200c. These results suggest that in aggressive breast cancers, as modeled by MDA-MB-231 cells, β-tubulin class III is a biomarker for cell survival mediated through ZEB1-induced tumor progression pathways.
authors.affiliation: School of Nursing, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA. slobert@umc.edu
authors.forename: Sharon
authors.initials: S
authors.lastname: Lobert
authors.forename: Mary E
authors.initials: ME
authors.lastname: Graichen
authors.forename: Kevin
authors.initials: K
authors.lastname: Morris
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014404:Tubulin / Q000235:genetics*; D015854:Up-Regulation; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D018398:Homeodomain Proteins; D035683:MicroRNAs; D012333:RNA, Messenger; D014157:Transcription Factors; D014404:Tubulin; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D017239:Paclitaxel