Exon-level microarray analyses identify alternative splicing programs in breast cancer

Anna Lapuk, Henry Marr, Lakshmi Jakkula, Helder Pedro, Sanchita Bhattacharya, Elizabeth Purdom, Zhi Hu, Ken Simpson, Lior Pachter, Steffen Durinck, Nicholas Wang, Bahram Parvin, Gerald Fontenay, Terence Speed, James Garbe, Martha Stampfer, Hovig Bayandorian, Shannon Dorton, Tyson A. Clark, Anthony SchweitzerAndrew Wyrobek, Heidi Feiler, Paul Spellman, John Conboy, Joe W. Gray

Research output: Contribution to journalArticle

86 Scopus citations

Abstract

Protein isoforms produced by alternative splicing (AS) of many genes have been implicated in several aspects of cancer genesis and progression. These observations motivated a genome-wide assessment of AS in breast cancer. We accomplished this by measuring exon level expression in 31 breast cancer and nonmalignant immortalized cell lines representing luminal, basal, and claudin-low breast cancer subtypes using Affymetrix Human Junction Arrays. We analyzed these data using a computational pipeline specifically designed to detect AS with a low false-positive rate. This identified 181 splice events representing 156 genes as candidates for AS. Reverse transcription-PCR validation of a subset of predicted AS events confirmed 90%. Approximately half of the AS events were associated with basal, luminal, or claudin-low breast cancer subtypes. Exons involved in claudin-low subtype-specific AS were significantly associated with the presence of evolutionarily conserved binding motifs for the tissue-specific Fox2 splicing factor. Small interfering RNA knockdown of Fox2 confirmed the involvement of this splicing factor in subtype-specific AS. The subtype-specific AS detected in this study likely reflects the splicing pattern in the breast cancer progenitor cells in which the tumor arose and suggests the utility of assays for Fox-mediated AS in cancer subtype definition and early detection. These data also suggest the possibility of reducing the toxicity of protein-targeted breast cancer treatments by targeting protein isoforms that are not present in limiting normal tissues.

Original languageEnglish (US)
Pages (from-to)961-974
Number of pages14
JournalMolecular Cancer Research
Volume8
Issue number7
DOIs
StatePublished - Jul 2010

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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    Lapuk, A., Marr, H., Jakkula, L., Pedro, H., Bhattacharya, S., Purdom, E., Hu, Z., Simpson, K., Pachter, L., Durinck, S., Wang, N., Parvin, B., Fontenay, G., Speed, T., Garbe, J., Stampfer, M., Bayandorian, H., Dorton, S., Clark, T. A., ... Gray, J. W. (2010). Exon-level microarray analyses identify alternative splicing programs in breast cancer. Molecular Cancer Research, 8(7), 961-974. https://doi.org/10.1158/1541-7786.MCR-09-0528