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Mol Cancer Res. 2010 Jul;8(7):961-74. doi: 10.1158/1541-7786.MCR-09-0528. Epub 2010 Jul 6.

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

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1
Life Sciences Division, Lawrence Berkeley National Laboratory, University of California at Berkeley, Berkeley, California 94720, USA. alapuk@prostatecentre.com

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.

PMID:
20605923
PMCID:
PMC2911965
DOI:
10.1158/1541-7786.MCR-09-0528
[Indexed for MEDLINE]
Free PMC Article
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