title: MicroRNA 9-3p targets β1 integrin to sensitize claudin-low breast cancer cells to MEK inhibition.
abstract: MEK1/2 inhibitors such as AZD6244 are in clinical trials for the treatment of multiple cancers, including breast cancer. Targeted kinase inhibition can induce compensatory kinome changes, rendering single therapeutic agents ineffective. To identify target proteins to be used in a combinatorial approach to inhibit tumor cell growth, we used a novel strategy that identified microRNAs (miRNAs) that synergized with AZD6244 to inhibit the viability of the claudin-low breast cancer cell line MDA-MB-231. Screening of a miRNA mimic library revealed the ability of miR-9-3p to significantly enhance AZD6244-induced extracellular signal-regulated kinase inhibition and growth arrest, while miR-9-3p had little effect on growth alone. Promoter methylation of mir-9 genes correlated with low expression of miR-9-3p in different breast cancer cell lines. Consistent with miR-9-3p having synthetic enhancer tumor suppressor characteristics, miR-9-3p expression in combination with MEK inhibitor caused a sustained loss of c-MYC expression and growth inhibition. The β1 integrin gene (ITGB1) was identified as a new miR-9-3p target, and the growth inhibition seen with small interfering RNA knockdown or antibody blocking of ITGB1 in combination with MEK inhibitor phenocopied the growth inhibition seen with miR-9-3p plus AZD6244. The miRNA screen led to identification of a druggable protein, ITGB1, whose functional inhibition synergizes with MEK inhibitor.
authors.affiliation: Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors.forename: Jon S
authors.initials: JS
authors.lastname: Zawistowski
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakamura
authors.forename: Joel S
authors.initials: JS
authors.lastname: Parker
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Granger
authors.forename: Brian T
authors.initials: BT
authors.lastname: Golitz
authors.forename: Gary L
authors.initials: GL
authors.lastname: Johnson
mesh_terms: D020413:3' Untranslated Regions; D001562:Benzimidazoles / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation; D057167:Claudins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D035683:MicroRNAs / Q000235:genetics*; D011728:Pyridones / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology
chemical_list: D020413:3' Untranslated Regions; C517975:AZD 6244; D001562:Benzimidazoles; D057167:Claudins; D004791:Enzyme Inhibitors; D019012:Integrin beta1; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D020930:MAP Kinase Kinase Kinases