title: Gene expression profiling reveals epithelial mesenchymal transition (EMT) genes can selectively differentiate eribulin sensitive breast cancer cells.
abstract: OBJECTIVE
  Eribulin mesylate is a synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B. Eribulin is a mechanistically unique inhibitor of microtubule dynamics. In this study, we investigated whether selective signal pathways were associated with eribulin activity compared to paclitaxel, which stabilizes microtubules, based on gene expression profiling of cell line panels of breast, endometrial, and ovarian cancer in vitro.
  
  
  RESULTS
  We determined the sets of genes that were differentially altered between eribulin and paclitaxel treatment in breast, endometrial, and ovarian cancer cell line panels. Our unsupervised clustering analyses revealed that expression profiles of gene sets altered with treatments were correlated with the in vitro antiproliferative activities of the drugs. Several tubulin isotypes had significantly lower expression in cell lines treated with eribulin compared to paclitaxel. Pathway enrichment analyses of gene sets revealed that the common pathways altered between treatments in the 3 cancer panels were related to cytoskeleton remodeling and cell cycle regulation. The epithelial-mesenchymal transition (EMT) pathway was enriched in genes with significantly altered expression between the two drugs for breast and endometrial cancers, but not for ovarian cancer. Expression of genes from the EMT pathway correlated with eribulin sensitivity in breast cancer and with paclitaxel sensitivity in endometrial cancer. Alteration of expression profiles of EMT genes between sensitive and resistant cell lines allowed us to predict drug sensitivity for breast and endometrial cancers.
  
  
  CONCLUSIONS
  Gene expression analysis showed that gene sets that were altered between eribulin and paclitaxel correlated with drug in vitro antiproliferative activities in breast and endometrial cancer cell line panels. Among the panels, breast cancer provided the strongest differentiation between eribulin and paclitaxel sensitivities based on gene expression. In addition, EMT genes were predictive of eribulin sensitivity in the breast and endometrial cancer panels.
authors.affiliation: Biomarkers and Personalized Medicine Core Function Unit, Eisai Product Creation Systems, Eisai Inc., Andover, Massachusetts, United States of America.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Dezső
authors.affiliation: Biomarkers and Personalized Medicine Core Function Unit, Eisai Product Creation Systems, Eisai Inc., Andover, Massachusetts, United States of America.
authors.forename: Judith
authors.initials: J
authors.lastname: Oestreicher
authors.affiliation: Biomarkers and Personalized Medicine Core Function Unit, Eisai Product Creation Systems, Eisai Inc., Andover, Massachusetts, United States of America.
authors.forename: Amy
authors.initials: A
authors.lastname: Weaver
authors.affiliation: Biomarkers and Personalized Medicine Core Function Unit, Eisai Product Creation Systems, Eisai Inc., Andover, Massachusetts, United States of America.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Santiago
authors.affiliation: Biomarkers and Personalized Medicine Core Function Unit, Eisai Product Creation Systems, Eisai Inc., Andover, Massachusetts, United States of America.
authors.forename: Sergei
authors.initials: S
authors.lastname: Agoulnik
authors.affiliation: Biomarkers and Personalized Medicine Core Function Unit, Eisai Product Creation Systems, Eisai Inc., Andover, Massachusetts, United States of America.
authors.forename: Jesse
authors.initials: J
authors.lastname: Chow
authors.affiliation: Biomarkers and Personalized Medicine Core Function Unit, Eisai Product Creation Systems, Eisai Inc., Andover, Massachusetts, United States of America.
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Oda
authors.affiliation: Biomarkers and Personalized Medicine Core Function Unit, Eisai Product Creation Systems, Eisai Inc., Andover, Massachusetts, United States of America.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Funahashi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D005663:Furans / Q000494:pharmacology* / Q000627:therapeutic use; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007659:Ketones / Q000494:pharmacology* / Q000627:therapeutic use; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use; D000095662:Polyether Polyketides
chemical_list: D000970:Antineoplastic Agents; D005663:Furans; D007659:Ketones; D017239:Paclitaxel; C490954:eribulin; D000095662:Polyether Polyketides