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Effects of β4 integrin expression on microRNA patterns in breast cancer
Kristin D. Gerson, V. S. R. Krishna Maddula, Bruce E. Seligmann, Jeffrey R. Shearstone, Ashraf Khan, Arthur M. Mercurio


The integrin α6β4 is defined as an adhesion receptor for laminins. Referred to as ‘β4’, this integrin plays a key role in the progression of various carcinomas through its ability to orchestrate key signal transduction events and promote cell motility. To identify novel downstream effectors of β4 function in breast cancer, microRNAs (miRNAs) were examined because of their extensive links to tumorigenesis and their ability to regulate gene expression globally. Two breast carcinoma cell lines and a collection of invasive breast carcinomas with varying β4 expression were used to assess the effect of this integrin on miRNA expression. A novel miRNA microarray analysis termed quantitative Nuclease Protection Assay (qNPA) revealed that β4 expression can significantly alter miRNA expression and identified two miRNA families, miR-25/32/92abc/363/363-3p/367 and miR-99ab/100, that are consistently downregulated by expression of this integrin. Analysis of published Affymetrix GeneChip data identified 54 common targets of miR-92ab and miR-99ab/100 within the subset of β4-regulated mRNAs, revealing several genes known to be key components of β4-regulated signaling cascades and effectors of cell motility. Gene ontology classification identified an enrichment in genes associated with cell migration within this population. Finally, gene set enrichment analysis of all β4-regulated mRNAs revealed an enrichment in targets belonging to distinct miRNA families, including miR-92ab and others identified by our initial array analyses. The results obtained in this study provide the first example of an integrin globally impacting miRNA expression and provide evidence that select miRNA families collectively target genes important in executing β4-mediated cell motility.


  • Competing interests Kristin Gerson, Jeffrey Shearstone, Ashraf Khan, and Arthur Mercurio declare that there are no competing interests. Bruce Seligmann works in a leadership role for, and owns stock in, HTG Molecular Diagnostics, Inc., the company that produces and markets the qNPA assay. Krishna Maddula works as a Staff Scientist for, and owns stock in, HTG Molecular Diagnostics, Inc. Bruce Seligman and Krishna Maddula have no affiliation with, nor do they consult with, the University of Massachusetts. The qNPA assay was carried out using funds from the Arizona Science Foundation through a grant to the University of Arizona, David Galbraith, PI, for which HTG Molecular Diagnostics, Inc. is the industry collaborator.

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